Dermal adipogenesis protects against neutrophilic skin inflammation

Dermal adipogenesis protects against neutrophilic skin inflammation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Dermal adipogenesis protects against neutrophilic skin inflammation Ling-juan Zhang, Ling-juan Zhang, Ling-juan Zhang, Tian Xia, Tian Xia, and 46 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4346630/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Jun, 2025 Read the published version in Cellular & Molecular Immunology → Version 1 posted 12 You are reading this latest preprint version Abstract The skin’s immune response to danger signals involves rapid recruitment of neutrophils, but their excessive accumulation leads to inflammatory skin diseases, such as psoriasis, and how skin resident cells tolerate neutrophilic inflammation is poorly understood. Dermal white adipose tissue (dWAT) is an emerging component of the skin's immune barrier, but its role in controlling skin inflammation remains under-studied. Here, using an imiquimod-induced psoriasis mouse model, we observed a dynamic coupling between dermal adipogenesis, neutrophil infiltration and regression. During the early inflammatory phase, dWAT repopulates with PDGFRA + preadipocytes that secrete CXCL1 and SAA3, attracting and activating CXCR2 + neutrophils. These neutrophils further activate preadipocytes through IL1β-IL1R signaling, establishing a self-sustaining inflammatory loop. Prolonged activation of pAds triggers PPARγ-dependent adipogenesis, leading to the formation of early adipocytes that secrete lipids exerting potent anti-inflammatory activity against myeloid cells, thereby aiding in inflammation resolution. Inhibition of adipogenesis, via targeted inhibition of PPARγ, through either pharmacological or genetic approaches, disrupts the formation of early adipocytes and prevents neutrophil regression and inflammation resolution. Analysis of human psoriatic cells identified a dFB subpopulation enriched with preadipocyte, IL1-pathway, and inflammatory gene signatures. Furthermore, transcriptomic analyses revealed a negative correlation between neutrophil-related inflammatory response with dermal adipogenesis response in generalized pustular psoriasis. Together, this study highlights the distinct roles of adipogenic fibroblasts and early adipocytes in initiating and resolving skin inflammation and suggests that promoting the differentiation of proinflammatory fibroblasts into anti-inflammatory early adipocytes could open avenues for the treatment of neutrophil-related inflammatory skin diseases, such as psoriasis and ulcers. Biological sciences/Immunology/Inflammation Biological sciences/Cell biology/Cell signalling/Stress signalling Biological sciences/Immunology/Inflammation Biological sciences/Cell biology/Cell signalling/Stress signalling Biological sciences/Immunology/Inflammation Biological sciences/Cell biology/Cell signalling/Stress signalling Skin inflammation Psoriasis Neutrophils Inflammation resolution Fibroblasts Adipogenesis Adipocytes Preadipocytes IL1 PPARγ Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction The skin, situated at the interface between the body and the environment, is continuously exposed to pathogens, toxins, allergens, and mechanical insults. Neutrophils, the most abundant circulating leukocytes in the body, are swiftly recruited to sites of infection and/or inflammation by chemotactic factors to eliminate pathogens and cellular debris 1,2 . However, prolonged activation and accumulation of neutrophils result in excessive production of reactive oxygen species (ROS), amplification of inflammatory responses, and initiation of autoimmunity, culminating in tissue damage and/or the onset of autoimmune skin conditions such as psoriasis and various skin ulcers 3–7 . Neutrophil accumulation in the skin is considered a hallmark characteristic of the early stages of psoriasis 5 , a chronic inflammatory skin disease affecting 2–3% of the global population. Psoriatic neutrophils play a significant role in maintaining the immune response in psoriasis 8 , and an excessive presence of neutrophils is a defining feature of generalized pustular psoriasis (GPP), an aggressive and potentially life-threatening form of the condition. GPP is characterized by the emergence of multiple sterile neutrophilic pustules over extensive areas of the skin 9,10 . Targeting and depleting neutrophils have shown promise in ameliorating clinical symptoms in patients with GPP who have not responded to conventional psoriasis therapies 11 , underscoring the pivotal role of neutrophils in driving GPP pathology. Neutrophil extracellular traps (NETs) promote the differentiation of T cells from human peripheral blood mononuclear cells into the IL17 + (TH17) subtype 12 . Moreover, neutrophil exosomes can be internalized by keratinocytes, triggering the expression of proinflammatory molecules 13 . Additionally, matrix metallopeptidase 9 (MMP9) released from neutrophils enhances cutaneous vascular dilation and permeability, exacerbating psoriasis 14 . A comprehensive understanding of the innate immune mechanisms governing neutrophil infiltration and activation, as well as the resolution of neutrophilic inflammation in the skin, is urgently required to develop anti-inflammatory therapies targeting neutrophil-related skin inflammatory diseases. The skin is a multilayered organ comprising the epidermis, dermis, and highly plastic dermal white adipose tissue (dWAT), which rapidly expands or regresses in response to various stimuli 15–19 . Upon deep skin bacterial infection, preadipocytes (pAds) rapidly expand and differentiate into early adipocytes that abundantly secrete the antimicrobial peptide protein CAMP to limit bacterial growth 18,19 , a response termed dermal reactive adipogenesis 20 . In contrast, mature adipocytes lose the ability to produce CAMP, which contributes to the increased susceptibility of obese individuals to skin bacterial infection 19 . Recent advances in single-cell RNA-seq have identified highly heterogeneous adipocyte-lineage cells, including committed preadipocytes and pluripotent adipocyte progenitors (AP) from the reticular dermis and/or hypodermal interstitium 15 . During skin development and wound healing, the commitment and differentiation of APs to pAd/adipocytes are controlled by the inflammatory factor IL1β released from myeloid cells, including neutrophils 15 , indicating that a cross-talk between adipocyte-lineage cells and neutrophils may exist and play a role in shaping skin inflammation during psoriasis pathogenesis. In this study, we aimed to investigate the roles of adipocyte-lineage cells, including adipogenic fibroblasts (preadipocytes) and adipocytes, in modulating neutrophilic inflammation in an animal model of psoriasis. Utilizing single-cell, single-nuclei, and multiple in vivo and in vitro co-culture functional models, we explored the cellular and molecular mechanism underlying the interactions between preadipocytes, adipocytes, and neutrophils. To assess the clinical relevance of our findings, we analyzed single-cell and bulk-sequencing databases derived from human psoriatic skin samples. These data uncover a previously unrecognized role of dermal adipocyte lineage cells in regulating neutrophilic inflammation during the pathogenesis of psoriasis. Results Dermal adipogenesis is dynamically coupled with the initiation and resolution of neutrophilic skin inflammation in the imiquimod-induced psoriasis mouse model Infiltration of neutrophils is considered the hallmark of the onset of psoriatic inflammation 21 . Immunostaining of human skin samples showed that myeloperoxidase-positive (MPO + ) neutrophils were found in close proximity to vimentin-positive (VIM + ) fibroblasts in the dermis of patients with plaque psoriasis (PV) (Fig. 1 A). Furthermore, the dermis from patients with generalized pustular psoriasis (GPP) exhibited an excessive accumulation of neutrophils around fibroblasts (Fig. 1 A). These findings suggest that aberrant activation of dermal fibroblasts may contribute to the activation and accumulation of neutrophils, potentially driving the pathogenesis of psoriasis. To gain insight into the dermal mechanism of neutrophil activation, we utilized the imiquimod (IMQ)-induced psoriasis-like mouse model, wherein neutrophil infiltration plays a pivotal role in the pathogenesis of skin inflammation 13,22,23 . As shown in Fig. 1 B-C, daily application of IMQ led to the progression of skin erythema, thickening, and scaling continued steadily up to 6 days post-treatment ( p.t. ), whereas these clinical manifestations began to resolve from 6 ~ 10 days p.t. , indicating the development of self-tolerance to IMQ over prolonged exposure. Histological analysis (Fig. 1 C-D, S1A-C) revealed a rapid reduction of the dWAT layer by day 2 p.t. , followed by a pronounced re-expansion of dWAT, where neutrophils characterized by their distinctive multi-lobulated nuclei 24 were detected at day 3 p.t. ; re-growth of mature adipocytes occurred from day 6 to 10 p.t. , coinciding with inflammation resolution. Analysis of neutrophils, marked by high level of Ly6G and CD11B expression 25,26 (Fig. S1 D-F), confirmed that neutrophil infiltration peaked between 3 and 6 p.t. . Immunostaining to ascertain the spatial relationship between dWAT cells and neutrophils found that FABP4 + adipocytes were rapidly lost by 3 p.t. , and concurrently Ly6G + neutrophils and PDGFRA + fibroblasts specifically co-populated the dWAT layer, with a peak in their presence observed at day 3 p.t. (Fig. 1 F-G). Subsequently, from day 6 to 10 p.t. , there was a repopulation of FABP4 + adipocytes within the dWAT, coinciding with a clearance of neutrophils from the skin (Fig. 1 F-G). Lipid staining analyses, conducted to evaluate changes of lipogenesis (Fig. 1 H, Fig. S1 G), indicated a reduction in lipid-laden adipocyte size on day 3, with a subsequent re-expansion by day 6 p.t.. Quantitative analysis of CAV1 + PLIN1 + adipocytes revealed a transient decrease in the number of large, mature adipocytes (> 1000 µm 2 ) on day 3 p.t., accompanied by a rise in the number of small adipocytes (< 500 µm 2 ) observed on both days 3 and 6 p.t. (Fig. S1 H-I, Fig. 1 I). Moreover, there was a notable regeneration of PDGFRA + fibroblasts within the dWAT region (Fig. 1 J). Additionally, fibroblasts derived from IMQ-treated skin samples (p.t. day 3 or 6) exhibited an enhanced adipogenic potential in vitro (Fig. 1 J-K). Collectively, these findings depict a two-step adipogenic response triggered by the IMQ application. In the early phase of inflammation progression, dWAT is repopulated with PDGFRA + preadipocytes (pAds), along with neutrophils. Subsequently, a re-expansion of lipid-ladened adipocytes coincides with the regression of neutrophils as the inflammation enters its resolution phase. Defining the immune response of Pdgfra + dermal fibroblasts by scRNAseq To elucidate the cell type-specific immune responses underlying IMQ-induced skin inflammation, we performed single-cell RNA sequencing (scRNA-seq) analysis on both control and IMQ-treated skin samples. The analysis led to the identification of 27 distinct cell clusters, which were categorized into various cell types such as dFBs, keratinocytes (KC), neutrophils (NEU), macrophages (MAC), and T cells, based on the expression of established marker genes (Fig. 2 A-B, Fig. S2A-C). Through differential gene expression analysis 27 , we identified the most differentially upregulated genes across these cell types. Notably, in dermal fibroblasts, Saa3 and Prg4 were markedly upregulated; in keratinocytes, S100a8 and Krt6a were the top upregulated genes; T cells exhibited heightened expression of Il22 and Il17a/f ; neutrophils displayed increased expression of Cxcl2 ; and macrophages exhibited elevated expression of Chil3 (Fig. 2 C-D). To further characterize the immune response of fibroblasts, Pdgfra + dFBs were classified into seven sub-clusters (r1 ~ r7), denoted as reticular (RET), papillary (PAP), and follicular dFBs, as well as various adipocyte-lineage cell clusters, including adipose regulatory cells (Areg), adipocyte progenitors (AP), and pAds, based on the expression of established dFB marker genes (Fig. 2 E, S2D) 15 . Among all dFB sub-clusters, application of IMQ notably increased the relative abundance of adipocyte-lineage cell clusters (Fig. 2 F). Multiple independent cellular differentiation trajectory analyses, including Monocle trajectory analysis, CytoTRACE, and RNA velocity, consistently predicted that dFB_r2 APs were differentiating into dFB_r3 pAds (Fig. 2 G, S2E-F). Furthermore, both dFB_r2 and r3 cells showed a significant enrichment of preadipocyte or inflammatory gene signatures after IMQ treatment (Fig. 2 H-I, S2G-H), suggesting that IMQ application may promote the accumulation of proinflammatory AP/pAds in the skin. Following IMQ application, Saa3, Prg4, Lcn2, Cxcl1 , and Cxcl12 were identified as the most prominently upregulated genes in dFB_r2 and/or r3 cells, while Tnc was uniquely upregulated in dFB_r6 PAP/follicular cells (Fig. 2 J, S2I-J). Notably, Prg4 and Fabp4 were co-induced in the dFB_r2 cells, whereas Saa3 showed higher levels of induction in r3, r1, and r6 cells (Fig. 2 J, S2I-J). This differential expression pattern of Prg4 and Saa3 may reflect distinct activation states of pAds. Immunostaining analysis confirmed the presence of PRG4 + cells, which were exclusively localized to the dWAT layer, and these cells co-expressed PDGFRA and PLIN1 (Fig. 2 K, S2K), indicating that PRG4 marks activated pAds that are undergoing differentiation into PLIN1 + adipocytes. Additionally, SAA3 + cells, which also co-expressed PDGFRA, were abundantly detected not only within the dWAT but also in the reticular dermis and at the dermal-epidermal junction (DEJ) region in skin treated with IMQ (Fig. 2 L). Within the dWAT, SAA3 + cells co-expressed medium-to-low levels of PRG4 (Fig. S2L-M). In contrast, TNC expression was predominantly induced by IMQ in the DEJ and follicular regions, but not in the dWAT (Fig. 2 M). These immunostaining findings align with the gene expression pattern observed in the scRNAseq results (Fig. 2 J and S2J). Together, our findings suggest that IMQ application triggers a cascade of events that promote dermal adipogenesis. Specifically, Anxa3 + APs appear to be primed to differentiate into proinflammatory Saa3 + pAds or Prg4 + pAds that have the potential to differentiate into Fabp4 + adipocytes. Additionally, Saa3 + pAds may further differentiate into Saa3 + Tnc + dFBs within the DEJ region (Fig. 2 N). It is important to note that further research is required to validate these proposed differentiation trajectories of adipocyte-lineage cells during psoriasis pathogenesis. Neutrophils trigger the inflammatory response of dFBs through the IL1β-IL1R signaling axis GO pathway analysis identified IL1 and neutrophil chemotaxis as the most significantly upregulated pathways in dFB_r3 pAds following IMQ application (Fig. 3 A). Cell-chat analysis of the IL1b-IL1r1 signaling network pinpointed neutrophils as the primary source of the IL1 ligand, acting on IL1r expressed on dFB clusters (Fig. S3A). Violin plots further illustrated that neutrophils expressed the highest level of Il1b among all major cell types examined, whereas dFBs expressed the highest level of Il1r1 (Fig. 3 B). Immunostaining data revealed that IMQ application specifically induced IL1R1 expression in PDGFRA + dFBs within dWAT (Fig. 4 C, S4B). In vitro study also identified Saa3 and Cxcl1 as the most prominent inducible genes by IL1β in primary neonatal dFBs (Fig. 3 D), which are composed of over 90% PDGFRA + Ly6A + THY1 + APs/pAds (Fig. S3C). These findings imply that IL1β, released from neutrophils, may play a crucial role in activating dFBs during psoriasis pathogenesis. To validate the role of neutrophils in activating dFB, we systemically depleted neutrophils via intravenous injection of the Ly6G antibody (Fig. S3D-E). This depletion significantly reduced neutrophil infiltration into the skin and suppressed the development of psoriatic phenotypes induced by IMQ (Fig. 3 E-H, S3F). Moreover, IL1b expression was substantially reduced upon neutrophil depletion (Fig. 3 I), supporting the idea that neutrophils are a primary source of IL1β in IMQ-treated skin. Consequently, the IMQ-induced mRNA expression of Saa3 and Cxcl1 (Fig. 3 I), as well as protein expression of SAA3 in PDGFRA + dFBs (Fig. 3 J-K) were significantly diminished upon neutrophil depletion. To further validate the role of IL1 signaling in dFB activation, IL1r1 −/− (KO) and wildtype (WT) littermate mice were subjected to IMQ-application (Fig. 3 L, S3I). IL1r1 deficiency not only inhibited the progression of the psoriatic phenotype (Fig. 3 L-M), but also blocked IMQ-induced dWAT expansion (Fig. S3J, Fig. 3 N), SAA3 protein expression in PDGFRA + dFBs (Fig. 3 O-P, S3K), and mRNA expression of Saa3 and Cxcl1 (Fig. 3 Q). Collectively, these results underscore the critical function of neutrophils in the immune activation of pAds via the IL1β-IL1R1 signaling pathway during the progression of IMQ-induced skin inflammation. Neutrophils and dFBs engage in a bidirectional IL1β-IL1R and CXCL1-CXCR2 signaling circuit We identified Cxcl1 , a pivotal neutrophil chemotactic gene 28,29 , and Saa3 as the most highly expressed inflammatory genes inducible by IL1β in dFBs (Fig. 3 D). This prompted us to investigated the role of dFB-derived CXCL1 and/or SAA3 in driving neutrophil activation. scRNA-seq analysis showed that dFBs were the primary source of Cxcl1 , acting on Cxcr2 expressed by neutrophils, which reciprocally expressed Cxcl2 (Fig. 4 A-B). Immunostaining confirmed that CXCL1 was predominantly expressed in PDGFRA + dFBs located in the dWAT following IMQ treatment (Fig. 4 C, S4A). To further explore the cellular interactions between dFBs and neutrophils, we developed an in vitro co-culture system, in which conditioned medium was collected from IL1β-primed or control dFB (dFB IL1β -CM or dFB ctrl -CM) to assess its effect on neutrophils (Fig. 4 D). Our findings revealed that dFB IL1β -CM significantly upregulated the expression of Il1b, Cxcl2, and Nos2 in neutrophils (Fig. S4B). Notably, the addition of an anti-CXCL1 antibody reduced the induction of Il1b and Cxcl2 , though not Nos2 , in neutrophils (Fig. 4 E-F, S4C). In contrast, when dFB IL1β -CM was obtained from Saa3 knockdown dFBs, it led to a decrease in Nos2 expression with no significant effect on Il1b or Cxcl2 Nos2 (Fig. 4 G, Fig. S4F-G). Furthermore, dFB IL1β -CM was found to enhance neutrophil migratory activity in a transwell assay, and this effect was significantly attenuated by the anti-CXCL1 antibody (Fig. 4 H-I, S4H). In contrast, primary keratinocytes, while responsive to IL17A with an inflammatory response, did not show induced expression of Il1b , Cxcl1 , or other keratinocyte-specific inflammatory genes following treatment with either IL1β nor dFB IL1β -CM (Fig. S4I-L). These findings suggest that the CXCL1-IL1β signaling circuit is specific to the interaction between dFBs and neutrophils, rather than with keratinocytes. In vivo, the administration of an anti-CXCL1 antibody concurrently with IMQ treatment in mice substantially alleviated the manifestation of IMQ-induced psoriatic phenotypes (Fig. 4 J-L), reduced the recruitment of Ly6G + neutrophils to dWAT (Fig. 4 M), and diminished the expression of inflammatory genes associated with neutrophils or dFBs (Fig. 4 N, S4M). These results collectively indicate that IL1β-activated pAds can augment neutrophil chemotaxis and activation through the secretion of CXCL1 and/or SAA3, contributing to the establishment of a self-perpetuating inflammatory response in in the skin dermis. Prolonged skin inflammation prompts the differentiation of Preadipocytes to Adipocyte We next explored the mechanisms underlying the resolution of inflammation during extended imiquimod (IMQ) treatment. First, to determine whether Pdgfra + pAds can differentiate into adipocytes during the resolution phase of IMQ-induced skin inflammation, we induced CRE activity in Pdgfra -ERT2cre;mTmG mice by tamoxifen application during the initial days of IMQ application to label Pdgfra + dFBs with GFP (Fig. 5 A). At day 6 p.t., we observed co-expression of GFP and FABP4 in the dWAT of IMQ-treated skin (Fig. 5 A), supporting the differentiation of PDGFRA + pAd into FABP4 + adipocytes. Building upon our previous work that IL1R signaling activation in dFBs triggers a dermal adipogenesis response crucial for during skin development and wound regeneration 15 , we have now observed that while brief IL1β exposure induced an immediate inflammatory response in dFBs, extended treatment significantly upregulated Pparg , the key transcription factor driving adipogenesis 30 , along with other adipocyte-related genes (Fig. 5 B, S5A). Analysis of the transcriptomic changes during the in vitro adipogenesis process from dFBs/APs to adipocytes revealed a distinct sequence of molecular events. This included the commitment of Anxa3 + Thy1 hi dFBs to Pdgfra hi Ly6a hi pAds post-confluency, followed by differentiation into Camp + early adipocytes (eAd), and ultimately to Pparg hi mature adipocytes (Fig. 5 C). During this process, there was a rapid decline in the expression of IL1 pathway-related genes, Il1r1 and Cxcl1 , and a transient expression of Prg4 by differentiating pAds (Fig. 5 C). In vivo IMQ application mirrored these in vitro changes, showing an upregulation of Prg4 , identified as a marker for differentiating pAds, which preceded the induction of Camp, Pparg , and other adipocyte-related genes between days 6 and 10 of IMQ application. Concurrently, there was a significant suppression of inflammatory genes, including Cxcl1 , Saa3 , Il1b , and Cxcl2 (Fig. 5 D-E, S5B-C). Immunostaining confirmed robust PPARγ induction in dermal white adipose tissue (dWAT) 6 days post-IMQ application (Fig. 5 F). These findings suggest that a PPARγ-dependent adipocyte differentiation program is a critical component of the resolution phase of skin inflammation. Characterization of the immune response of Adipocytes by single-nuclei RNA sequencing To maximally captured adipocytes, which are largely lost through enzymatic digestion in scRNA-seq 31 , we next performed single-nuclei RNA sequencing (Sn-RNAseq) of IMQ-treated skin samples. Sn-RNAseq identified a distinct cluster of Pparg + adipocyte, representing 5% of the total cells (Fig. S5D-F). Further reclustering of fibroblast and adipocyte clusters delineated six sub-clusters (r0–r5), including Pparg hi Lpl + Adipoq + adipocytes (r2), Lpl + Pparg lo−med preadipocytes (r1), and various other dermal fibroblast clusters (Fig. 5 G-H, S5G). Pseudotime analysis predicted the differentiation trajectory from r1_pAds to r2_adipocytes (Fig. 5 I, S5H). Notably, r1_pAds exhibited the highest inflammatory scores and expressed high levels of Cxcl1 and Saa3 , whereas r2_adipocytes showed the lowest inflammatory scores and expressed genes associated with adipogenesis ( Camp, Adipoq , and Fabp4 ) but not inflammatory genes (Fig. 5 J-K), suggesting that the inflammatory response is suppressed in differentiating adipocytes. PPARγ-mediated preadipocyte differentiation is necessary for the resolution of skin inflammation To determine the role of PPARγ in mediating neutrophil clearance, we administered BADGE, a selective pharmacological inhibitor of PPARγ 19,32,33 , via intraperitoneal injection during IMQ application (Fig. 6 A). BADGE treatment led to an exacerbation of the psoriatic phenotype (Fig. 6 B-C), inhibited the formation of FABP4 + adipocytes in dWAT, and resulted in increased neutrophil infiltration and upregulation of neutrophil-associated inflammatory genes ( Il1b and Cxcl2 ) in IMQ-treated skin (Fig. 6 D-F, S6A-B). To block adipogenesis by deleting PPARγ in PDGFRA + pAds, we next generated tamoxifen (TAM)-inducible fibroblast-specific Pparg knockout mice, termed Pparg FB−iKO , by crossing Pparg flox/flox mice with Pdgfra -cre/ ERT mice (Fig. 6 G). TAM application to Pparg FB−iKO mice during IMQ-application specifically ablated the expression of PPARγ in dWAT (Fig. S6C), leading to an exacerbation of psoriatic clinical phenotypes (Fig. 6 H-I), inhibition of adipogenesis (Fig. 6 J, S6D) and Camp expression (Fig. 6 K), and increased expression of inflammatory genes ( Cxcl2, IL1b, Nos2 ) (Fig. 6 K, S6E). These results highlight the critical role of PPARγ in preadipocyte differentiation and the resolution of neutrophilic skin inflammation during topical IMQ application. Early adipocytes exhibit anti-inflammatory effects against myeloid cell activation We next investigated the therapeutic potential of adipocytes in countering inflammation-medidated by myeloid cells, including neutrophils and macrophages. Conditioned medium (CM) was collected from three stages of adipocyte differentiation: undifferentiated (undif) dFB/pAd, early adipocytes (eAd) secreting CAMP, and mature adipocytes (mAd) with elevated FABP4 secretion (Fig. 7 A). These CM samples were then used to treat neutrophils or peritoneal macrophages activated by FSL or LPS (Fig. 7 A and Fig. S7A). Notably, CM from eAd, but not undif or mAd, significantly reduced the expression of proinflammation genes Cxcl2, IL1b , and Nos2 in activated neutrophils and/or macrophages (Fig. 7 B-D, S7B), and induced anti-inflammatory M2-macrophage-associated genes, such as Chil3 and Cd163 34 , in activated macrophages (Fig. S7C-D). Subsequently, we explored the in vivo therapeutic effects of eAd-CM against IMQ-induced skin inflammation. eAd-CM i.d. injections substantially alleviated the development of psoriatic phenotypes (Fig. S7E-G), reduced the expression of inflammatory genes (Fig. S7H), and decreased infiltration of Ly6G + neutrophils in dWAT (Fig. S7I-J) in IMQ-treated skin. Moreover, eAd-CM suppressed IMQ-induced epidermal hyperplasia and the presence of Ki67 + proliferative epidermal cells (Fig. S7J-K), and inhibited the IMQ-mediated induction of Krt6a, Defb14, and Il17a (Fig. S7H). Hence, eAd-CM’s inhibitory effect on epidermal cell activation is likely due to its suppressive effect on myeloid cell activation. Early adipocyte-derived lipids are anti-inflammatory We observed that the anti-inflammatory substances in eAd-CM were heat-stable (Fig. 7 E, S7L-M), suggesting they are not protein-based. In addition, only the lipid fraction, but not the protein fraction of eAd-CM, exhibited inhibitory effects against LPS-induced Il1b, Cxcl2 , and Nos2 expression (Fig. 7 F-G, S7N), demonstrating that the anti-inflammatory substances in eAd-CM are lipids. To develop a topical approach to deliver eAd_lipids, we utilized Haliclona sp. spicules (SHS), microneedles derived from marine sponges, facilitating skin penetration of therapeutics even nanoparticles by overcoming barriers and creating nano-pores across the skin epithelium 35,36 . Topical application of lipids from eAd, in combination with SHS, effectively prevented the onset of IMQ-induced psoriatic features (Fig. 7 H-J), blocked the infiltration of Ly6G + neutrophils (Fig. 7 K), and reduced the number of epidermal Ki67 + cells (Fig. 7 K-L). Furthermore, it suppressed pro-inflammatory gene expression and restored the expression of claudin genes important for epidermal tight junctions (Fig. 7 M, S7O). These results underscore the role of early adipocytes in secreting lipids with anti-inflammatory properties to attenuate myeloid cell activation, thereby aiding in the resolution of inflammation during IMQ application. Preadipocyte Signature and IL1 Pathway Enrichment Characterize Proinflammatory Fibroblasts in Human Psoriasis Next, we sought to establish the relevance of our mouse findings to human psoriasis by reanalyzing single-cell RNA sequencing (sc-RNA-seq) data from patients with psoriasis and healthy controls 37 . Aligning with mouse data, PDGFRA + dFBs were identified as the main producers of IL1R1, CXCL1 , and PRG4 , with myeloid cells predominantly expressing IL1B in psoriatic lesions (Fig. 8 A). Reclustering of PDGFRA + dFBs resulted in nine dFB subclusters (r0–r8), and pseudotime analysis predicted that r1, r2, and r7 clusters were in the terminal state of cellular differentiation (Fig. 8 B-C, S8A). Notably, correlation analysis revealed that the human r1 and r2 dFB clusters were closely related to the murine IMQ-induced dFB_r3 cluster, which represents the pro-inflammatory pAds (Fig. 8 D). Additionally, dFB_r2 cells exhibited enrichment in pAd and inflammatory gene-set signatures (Fig. 8 E). Gene Ontology (GO) analysis identified pathways, including responses to IL1, WNT, and TGFβ, as the top enriched pathways associated with dFB_r2 cells in human psoriasis (Fig. 8 F). Given our previous findings that TGFβ and WNT are key inhibitors of dermal adipogenesis 15,18 , their overactivation may impede the transition of pro-inflammatory pAds into anti-inflammatory adipocytes, thereby potentially exacerbating dermal inflammation. To gain insight into the increased neutrophil infiltration in generalized pustular psoriasis (GPP) compared to plaque psoriasis (PV), we analyzed transcriptomic data from normal, PV, and GPP human skin samples (GSE79704) 38 . We found that GPP samples expressed higher levels of IL1B, CXCL1 , and key adipogenesis inhibitor genes WNT3 and TGFB1 , compared to normal and/or PV samples. In contrast, genes related to adipogenesis, including PPARG, PRG4, CEBPB , and FABP4 , were downregulated in GPP samples (Fig. 8 G, S8B). Furthermore, correlation analyses showed that IL1B expression positively correlated with CXCL1 and negatively with PPARG and PRG4 , while PPARG and PRG4 exhibited a positive correlation (Fig. 8 H, S8C). Discussion As an emerging component of the skin's immune barrier, dWAT undergoes substantial expansion and contraction during infection and/or wound healing, thereby contributing to innate immune antimicrobial defense and skin regeneration 15,16,18,19 . However, the function of dWAT in shaping the skin immune response under inflammatory conditions remains largely unexplored. In this study, we observed a rapid expansion of dWAT alongside the proliferation of PDGFRA + preadipocytes, which secrete CXCL1 to chemoattract CXCR2 + neutrophils. The neutrophils, in turn, release IL1β, which further activates pAds through IL1R. These interactions create a self-sustaining inflammatory loop within the dermis. Intriguingly, sustained activation of IL1R signaling in pAds leads to PPARγ-dependent adipogenesis, resulting in the formation of early adipocytes. These emerging adipocytes produce anti-inflammatory lipids that counteract neutrophilic inflammation. Notably, targeted inhibition of PPARγ, through either pharmacological or genetic approaches, prevents the formation of early adipocytes and impedes the resolution of inflammation. These findings elucidate a previous unrecognized mechanism by which resident cells develop self-tolerance to neutrophilic skin inflammation, involving the conversion of proinflammatory fibroblasts into anti-inflammatory adipocytes. Our study underscores the dynamic immunoregulatory function of dermal white adipose tissue (dWAT) in the pathogenesis of neutrophilic skin inflammation, particularly in the imiquimod (IMQ)-induced model, the most commonly used psoriasis mouse model 23 . Notably, the rapid expansion of dWAT has also been observed under other inflammatory conditions, particularly in contexts where neutrophil activity predominates, such as bacterial infection 18,19 and wounding 15,39 . The capacity of dWAT to perceive inflammatory signals hinges upon the expression of diverse cytokine receptors. Here, we demonstrate that pAds express high levels of IL1R, thereby enabling them to sense IL1β released by infiltrating neutrophils. This aligns with existing literature that positions dermal fibroblasts as pivotal sensors of IL1, particularly when released by damaged keratinocytes 40 . Furthermore, the Anxa3 + Ly6A + adipocyte progenitors identified in our study has been recognized as T(H)2-interacting fascial fibroblasts (TIFF) 41 . These hypodermal TIFFs expand in response to TH2 cytokines, thereby promoting Th2 T cell polarization and contributing to the formation of hypodermal fibrous bands 41 . Collectively, these studies suggest that lipogenic fibroblasts within dWAT, which is the skin’s deepest defensive layer, act as crucial sensors and immunomodulators, participating in the intricate cascade of inflammation orchestrated by IL1 and/or TH2 cytokines. The presence of neutrophils in skin lesions is a histopathological hallmark of psoriasis 5 . While keratinocytes release the chemokines CXCL1 and IL-8 to recruit neutrophils to the epidermis 42,43 , the dermal mechanism for neutrophil recruitment is less understood. In situ hybridization and immunostaining analysis of psoriatic skin sections revealed that while IL8 was primarily detected in the upper epidermis by keratinocytes, CXCL1 expression was also strongly expressed in the dermis 44 ,, suggesting a dermal source for this chemokine. This study demonstrate that the inflammatory PDGFRA + pAd are a prominent dermal source for CXCL1, which in turn acts on neutrophils to enhance IL1β and CXCL2 expression and to induce neutrophil chemotaxis. In addition, we identified SAA3, a major acute-phase protein produced during inflammation 45 , as a marker for pAds activated by IL1β. In mice, Saa3 encodes a functional SAA protein and is the major SAA isoform in inflammatory tissues 46,47 , and IL1 is found the major cytokine responsible for SAA3 induction through a NFKB-and C/EBP dependent mechanism 48–50 , aligning with our findings. SAA proteins possess cytokine-like properties, participating in cytokine synthesis, chemotaxis of myeloid cells, and activation of the inflammasome cascade 45,51 . SAA3 is also highly expressed in adipose tissue during hyperglycemia and obesity, promoting adipose tissue inflammation 52,53 . Our results showed that the knockdown of Saa3 in activated pAds reduced the ability of pAd to induce the expression of the NO synthase ( Nos2 ), but not IL1b and Cxcl2 in neutrophils, suggesting that pAds contribute to oxidative stress in neutrophils through SAA3 production. The topical application of imiquimod is a widely used acute model for psoriasis-like inflammation, but this model is limited by the development of self-tolerance after one-week of application as shown in this study and other studies 54,55 . Nevertheless, the precise mechanisms behind this acquired tolerance are not understood. In this study, we discovered that prolonged exposure of preadipocytes with IL1β eventually leads to the upregulation of PPARγ, which drives the differentiation of proinflammatory CXCL1 + SAA3 + preadipocytes into anti-inflammatory early adipocytes, thereby contributing to the resolution of psoriatic skin inflammation. These results are in line with our previous report, which showed that activating IL1R signaling in preadipocytes induces NFκB-dependent phosphorylation of CREB1, subsequently triggering the expression of CEBP/β and PPARγ to initiate adipogenesis during skin development and wound healing 15 . Stimulated PPARγ exerts its anti-inflammatory effect by binding to NFκB at NFκB target genes 56 such as Cxcl1 and Saa3 . Additionally, we identified PRG4, an extracellular matrix protein known for its role in reducing joint shear stress 57–59 , as a marker for differentiating pAds. PRG4 has an anti-inflammatory function; it can bind to toll-like receptors 2 and 4, potentially inhibiting their downstream signaling pathways and reducing the recruitment of proinflammatory macrophages 57–59 . Further research is necessary to fully understand the role of PRG4 in modulating the anti-inflammatory functions of differentiating preadipocytes in the context of psoriasis pathogenesis. Our data suggest that the dysregulation of lipogenic fibroblasts may play a role in the chronic inflammation associated with human psoriasis. In human skin, the dermal microvascular structures situated in the dermal-epidermal junction region are particularly enriched with CD34 + mesenchymal stem cells (MSC) 60 . These MSCs resembles murine Cd34 + APs residing in the perivascular niche, which is required to maintain their pluripotency 61–63 . By analyzing human psoriatic scRNAseq data, we identified a subset of dFBs that are enriched with pAd and IL1-pathway signatures, resembling the inflammatory pAd cluster observed in the IMQ-treated murine skin. A recent study utilizing single-cell and spatial RNA sequencing has identified a subset of SFRP2 + fibroblasts in psoriasis contributing to amplification of the immune network by adopting a proinflammatory phenotype, with IL1β identified as a primary driver of fibroblast inflammation 64 . SFRP2, recognized as an adipokine secreted from undifferentiated AP/pAd 65–67 , was found to be selectively expressed in APs among all dFB subsets (Fig. S2D). Notably, we found that human pAd cluster also co-enriched with pathways related to inhibitors of adipocyte differentiation, including WNT and TGFβ 15,18 , suggesting that the adipogenic differentiation of these cells into an anti-inflammatory state may be impeded in psoriasis. Consistent with this, we observed an inverse correlation between the expression levels of adipogenesis markers, including PRG4 , FABP4 , and/or PPARG , and markers of neutrophilic inflammation in human psoriasis. This correlation could potentially serve as a biomarker to distinguish between plaque psoriasis (PV) and generalized pustular psoriasis (GPP), the latter of which is characterized by excessive presence of neutrophils 9,38 . Our findings suggest that the suppression of the adipogenic potential in proinflammatory fibroblasts may be an intrinsic mechanism contributing to the relentless neutrophilic inflammation observed in GPP. We have demonstrated that early adipocytes, as opposed to mature adipocytes, secrete anti-inflammatory lipids that help to reduce neutrophilic inflammation. However, a limitation of our study is the yet unidentified nature of these specific bioactive lipids. Moreover, we observed an initial lipolysis event that precedes the re-expansion of dWAT and the subsequent differentiation of adipocytes during IMQ treatment (Fig. 1 ), but the functional significance of this initial lipolysis in the context of the adipocyte differentiation process remain to be elucidated. Lipolysis is recognized to be interconnected with de novo lipogenesis, as the free fatty acids (FA) released from the hydrolysis of triglycerides have the potential to be recycled into new lipids and these FA also act as ligands to activate PPARγ 68 . Future lipidomic study is required to determine the identity of the bioactive lipids secreted by early adipocytes, and to explore whether the initial lipolysis event facilitates subsequent de novo lipogenesis by supplying fatty acids. In summary, our study has discovered a previously unrecognized mechanism by which the skin develops a tolerance to neutrophilic inflammation. The exploration of strategies aimed at transitioning proinflammatory adipogenic fibroblasts into anti-inflammatory adipocytes, could represent a promising avenue for developing innovative treatments for neutrophil-driven skin disorders, such as psoriasis and ulcers. Materials and Methods Data and Code Availability The accession numbers for the raw data files of the scRNA-seq and snRNA-seq analyses reported in this paper are deposited in the GEO database under accession codes: GSE238086, GSE238085 Animals and animal cares: All animal experiments were approved by the Institutional Animal Care and Use Committee of Xiamen University. C57BL/6 mice, 7–9 weeks old, were purchased from GemPharmatech (Nanjing, China). Pdgfra- C re ERT2 mice (Stock No: 032770) and ROSA- mT/mG mice (Stock No: 07676) were originally purchased from Jackson laboratory. Pparg flox/flox mice were generously provided by professor Yuling Shi (Tongji University, Shanghai, China). Fibroblast specific Pparg knockout mice were generated by breeding Pparg flox/flox with Pdgfra- C re ERT2. Il1r1 −/− mice were generously provided by professor Jiahuai Han (Xiamen University, Xiamen, Fujian, China). All mice were bred and maintained in standard pathogen free environment of the Laboratory Animal Center in Xiamen University. Human skin sample collection and analysis: Fresh adult human full thickness skin biopsies, from age and sex matched healthy, psoriasis donors were collected by the department of dermatology at Shanghai Skin Disease hospital. Patients with psoriasis vulgaris or Generalized pustular psoriasis (GPP) were diagnosed based on their clinical appearance. All sample acquisitions were approved and regulated by Medical Ethics Committee of the Shanghai Skin Disease hospital (reference number No. 2023-04). All donors provided the informed consent before skin biopsies. Upon collection, these samples were directly fixed with PFA and then proceed for paraffin embedding for histological or immunofluorescent analyses. IMQ-induced Psoriasis-like mouse model and treatment procedures 7 ~ 9 weeks old C57BL/6 mice (sex-matched) were anesthetized using isoflurane, and dorsal skin was shaved, depilated, then topically applied with a dose of 45mg IMQ cream (5%, MedShine, 120503) over a 2 cm 2 surface area for 6 consecutive days. The severity of skin inflammation was evaluated daily using the Psoriasis Area and Severity Index (PASI) as described previously 69,70 . For lineage tracing of Pdgfra + dFBs, Pdgfra-Cre ERT2; mTmG mice were daily received an intraperitoneal injection of tamoxifen (TAM) (Sigma, T5648) dissolved in corn oil (Selleck, s6701) at 50mg/kg body weight for 4 consequent days during IMQ treatment. To deplete neutrophils, mice were intraperitoneally administrated with 50 µg of anti-LY6G (Biolegend, 127649) or IgG2a isotype control antibody (Biolegend, 400565) from one day after IMQ treatment to the end of the experiment. For CXCL1 blockade, 20 µg of anti-CXCL1 antibody (R& D Systems, MAB453) or rat IgG2A isotype control antibody (R&D Systems, MAB006) were injected intravenously at a 2-days interval starting from one day before IMQ treatment to the end of the experiment. To antagonize PPARγ signaling, mice were injected intraperitoneally with 30mg/kg of BADGE (Sigma, D3415) two days after IMQ treatment to the end of the experiment, and 10% DMSO in PBS was used as control. For in vivo application of eAd-CM, 200 µl of blank medium or eAd-CM were injected i.p. to mouse back skin during IMQ application. For topical application of eAd_lipids, 1 mg highly purified Sponge Haliclona sp. spicules (SHS) 35,36 was resuspended in 100 µl of lipid fractions isolated from blank medium or eAd-CM, and the mixture was then dripped onto IMQ-treated area of skin, followed by massaging dorsal skin for 2 min. Single-cell or Single-nuclei RNA library preparation and sequencing: Briefly, dorsal skin biopsies were collected from healthy control and IMQ-treated C57BL/6 mice, and skin biopsies were subjected to mincing and enzymatic digestion by collagenase D and DNase1 to isolate single cell as described previously 15,16,71 . Dead cells were removed using DeadCell Removal kit (Miltenyi Biotic,130-090-101) according to manufacturer’s instruction. To isolate single-nuclei, fresh skin tissues were preserved by snap freezing in liquid nitrogen, transferred to a dounce homogenizer, grinded into a homogenate in lysis buffer. Nuclei were extracted by repeated washes with nuclear resuspension buffer and sucrose cushion buffer, then isolated nuclei were further purified by DAPI staining and sorting. Live single cells or single nuclei were loaded on a 10x Genomics GemCode Single-cell instrument that generates single-cell Gel Bead-In-EMlusion (GEMs). Single-cell or single-nuclei libraries were prepared using Chromium Next GEM Single Cell 3’ Reagent Kits v3.1. cDNA libraries were sequenced on an Illumina Novaseq6000 platform (Illumina). Detailed methods for data processing, including quality control, unsupervised clustering, gene expression analysis, and bioinformatic analyses including Monocle pseudotime analysis, CytoTRACE analysis, RNA velocity analysis, muti-volcano differential expression analysis, gene-set enrichment score analysis, Pearson Correlation analysis, cell-chat signaling network analysis can be found in the supplemental method section. Single cell RNA libraries construction, sequencing and bioinformatic analysis was assisted by GENE DENOVO Inc (Guangzhou, China). Primary mouse dermal fibroblast isolation and in vitro adipocyte differentiation: Primary mouse dermal fibroblasts (dFBs) were isolated from neonatal or adult mouse skin by enzymatic digestion with dispase, Collagenase D, and DNAse1 as shown previously 16,71 . Isolated dFBs were cultured in growth medium (DMEM supplemented with 10% FBS and antibiotics/antimycotics) in a humidified incubator at 5% CO2 and 37°C under sterile conditions, and only passage 1 cells were used for experiment. To collect CM from IL1β-primed dFBs, cells were treated with IL1β for 2h and medium was replaced with fresh medium without IL1β for additional 48 hours before collection. To induce adipocyte differentiation, two days post-confluent dFB were switched to adipocyte differentiation medium containing 2 µM Dexamethasone, 250 µM IBMX, 200 µM Indomethacin and 10 µg/mL recombinant human insulin. Fresh differentiation medium was changed at day 3 then medium was switched to maintenance medium (growth medium supplemented with 10 µg/mL recombinant human insulin) to promote maturation and hypertrophy of differentiated adipocytes. Adipocytes were stained with Oil-red-O (ORO) to detect lipid-droplets as described previously 72 . The percentages of ORO-positive areas were quantified using ImageJ software. Adipocyte conditioned medium collection and lipid extraction Adipocytes at indicated differentiation days were maintained in serum free medium containing 10 µg/mL recombinant human insulin for 3 days before conditioned medium (CM) was collected and centrifuged to remove cell debris. To heat inactivate protein, Ad-CM was heated at 95℃ for 15 mins on heat block. Proteins and lipids extraction was performed as described by Matyash (Matyash et al., 2008). Briefly, Methyl tert-Butyl Ether (MTBE)/Methanol was added to CM (10:3:2.5, v/v/v) and the mixture were vortexed for 1 min before centrifugation for 15min at 3,000 g. The lipid-containing upper layer and the protein precipitation were collected separately, and then dried under a gentle stream of nitrogen gas at 37˚C followed by resuspension in DMEM/F12 to an identical final volume for cell treatment or in vivo application. Primary neutrophil and macrophage isolation and in vitro culture: Primary bone marrow-derived neutrophils and peritoneal macrophages were isolated and cultured as described in the supplemental method section. For co-culture assays, neutrophils or macrophages were pretreated with CM collected from dFBs or adipocytes (50% volume), then stimulated without or with FSL (50 ng/mL) for 6 hours or LPS (500 ng/mL) for 12 hours. To block CXCL1 activity, adipocyte-conditioned medium was pre-incubated with anti-CXCL1 neutralizing antibody (R&D Systems, MAB453) or rat IgG2A isotype control antibody (R&D Systems, MAB006) for one hour at 37°C before the CM was applied to neutrophils. For neutrophil transmigration assay, neutrophils were isolated from ROSA-mT/mG mice and were placed to the top of the Transwell® inserts, and dFB-CM were added to the bottom of each well. 2 hours after the co-culture, neutrophils transmigrated to the lower chamber were fixed and stained with FITC-Ly6G antibody (eBioscience, 11593182). The percentage of Tomato + Ly6G + neutrophils were imaged and counted by confocal fluorescence microscopy. Quantification and statistical analysis Experiments were repeated at least 3 times with similar results and the data were statistically analyzed using GraphPad Prism (version 9.0.0). Quantification analyses of Immunofluorescence sections showing the fluorescence integrated intensity of indicated fluorophores were performed by ImageJ (version 1.53). Quantified intensity profiles showing signals from indicated fluorescent channels across skin sections (from top to bottom) is adapted from publications 73,74 . Statistical significance was determined using Student’s unpaired two-tailed t-test to compare two conditions or one-way ANOVA for multiple comparisons. The probability values of < 0.05 were considered statistically significant (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001). Declarations CONFLICT OF INTERESTS All authors declare no competing interests. AUTHOR CONTRIBUTIONS Conceptualization, T.X, W.Z, R.W., M.C., and L.Z.; methodology, T.X, W.Z, R.W., X.Z., R.X., C.Z., W.L., and L.Z.; investigation, T.X, W.Z, R.W., X.Z., R.X., X.H., S.W., Yanhang.L., J.L., Youxi.L., Yiman.L., Z.G., and W.L.; resources, M.C., J.L., and Y.S.; data curation, T.X, W.Z, R.W., and L.Z.; writing-original draft, T.X, W.Z, R.W., and L.Z.; writing-review and editing, M.C., J.L., Y.S., and L.Z.; supervision, L.Z. ACKNOWLEDGMENTS L-J. Z. is supported by National Key R&D Program of China (2023YFC2508102) and NSFC (82373879 and 81971551). We thank Dr. Jiahuai Han from Xiamen University for providing the IL1r1 −/− mice and Dr. Yuling Shi from Fudan University for providing the Pparg-floxed mice. We thank the flow-cytometry and confocal microscopic core facility at Xiamen university for flow-cytometry, sorting and imaging studies. References Peiseler, M. & Kubes, P. More friend than foe: the emerging role of neutrophils in tissue repair. 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Biochim Biophys Acta 1848 , 1308-1318 (2015). https://doi.org:10.1016/j.bbamem.2015.03.001 Additional Declarations (Not answered) Supplementary Files 050124SupplementalfilesCombined.pdf Cite Share Download PDF Status: Published Journal Publication published 23 Jun, 2025 Read the published version in Cellular & Molecular Immunology → Version 1 posted Editorial decision: revise 08 Jul, 2024 Review # 3 received at journal 06 Jul, 2024 Review # 2 received at journal 20 Jun, 2024 Reviewer # 3 agreed at journal 14 Jun, 2024 Review # 1 received at journal 13 Jun, 2024 Reviewer # 2 agreed at journal 03 Jun, 2024 Reviewer # 1 agreed at journal 29 May, 2024 Reviewers invited by journal 08 May, 2024 Editor assigned by journal 06 May, 2024 Submission checks completed at journal 06 May, 2024 First submitted to journal 06 May, 2024 Unknown event 30 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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White dotted lines separate the epidermis from the dermis. Scale bar, 200 μm.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eB\u003c/strong\u003e) Schematic diagram for the imiquimod (IMQ)-induced psoriasis-like mouse model.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eC\u003c/strong\u003e) Skin lesion images and (\u003cstrong\u003eD\u003c/strong\u003e) Psoriasis Area Severity Index (PASI) scores showing the progression and resolution of skin inflammation.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eE\u003c/strong\u003e) Representative Hematoxylin-Erosin (H\u0026amp;E) staining of mice skin.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eF\u003c/strong\u003e) Representative immunostaining of FABP4 (red; adipocytes), Ly6G (green; neutrophils), PDGFRA (blue, fibroblasts), and DAPI (white; nuclei). Scale bar, 200 μm. (\u003cstrong\u003eG\u003c/strong\u003e) Quantified intensity profiles of Fig. 1F showing signals from all three fluorescent channels across skin from epidermis to dWAT (representative of n=3/group).\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eH\u003c/strong\u003e) Whole-mount Oil-red-O (ORO) staining. Scale bar, 100 μm.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eI\u003c/strong\u003e) Quantification of the number and size distribution of Caveolin\u003csup\u003e+\u003c/sup\u003e and Perilipin\u003csup\u003e+\u003c/sup\u003e adipocytes on ctrl, day 3 and day 6 of IMQ application as indicated (staining images are in Fig. S1H; n=8~20 areas/group).\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eJ\u003c/strong\u003e) Representative immunostaining of PDGFRA (red), PLIN1 (green), and DAPI (white; nuclei). Scale bar, 100 μm.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eK-L\u003c/strong\u003e) Primary dermal fibroblasts isolated from control or IMQ (day 3 and day 6) skin were subjected to adipocyte differentiation. ORO staining (\u003cstrong\u003eK\u003c/strong\u003e) and quantified bar graphs (n=3/group)) (\u003cstrong\u003eL\u003c/strong\u003e) showing the percentage of ORO\u003csup\u003e+\u003c/sup\u003e adipocytes.\u003c/p\u003e\n\u003cp\u003eAll error bars indicate mean ± SEM. *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"050124PSOanddWATmanuscriptmainfiguresPage1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4346630/v1/cd02ebe17f54ae4155c8231b.jpg"},{"id":56682534,"identity":"f976fb8c-da4f-4172-8153-11c14f7ab237","added_by":"auto","created_at":"2024-05-17 18:26:43","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4418457,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDefining the immune response of\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003e Pdgfra\u003c/strong\u003e\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u003cstrong\u003e+\u003c/strong\u003e\u003c/em\u003e\u003c/sup\u003e\u003cstrong\u003e dermal fibroblasts by scRNAseq\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e: Schematic of single-cell RNA sequencing (scRNA-seq) preparation of dorsal skin cells isolated from Ctrl and IMQ-induced mice.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e: tSNE projection of all 16,923 sequenced mouse skin cells, showing cell distribution by clusters.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e: Violin plots showing indicated the expression of indicated genes in various cell types from control (blue) and IMQ (red) skin.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD\u003c/strong\u003e: Differential gene expression analysis showing top upregulated genes in various cell types after IMQ application.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eE-J\u003c/strong\u003e: \u003cem\u003ePdgfra\u003c/em\u003e\u003csup\u003e\u003cem\u003e+\u003c/em\u003e\u003c/sup\u003e dFBs were reclustered into r1~r7 sub-clusters. (\u003cstrong\u003eE\u003c/strong\u003e) UMAP plots showing cell distribution. (\u003cstrong\u003eF\u003c/strong\u003e) Stacked bar graphs showing the percentage of each cluster. (\u003cstrong\u003eG\u003c/strong\u003e) Monocle analysis showing the differentiation pseudotime values projected to UMAP plot. Signature score distribution shown on bar graphs (\u003cstrong\u003eH\u003c/strong\u003e)\u003cstrong\u003e \u003c/strong\u003eor UMAP (\u003cstrong\u003eI\u003c/strong\u003e) for preadipocyte (pAd) or inflammatory signatures. (\u003cstrong\u003eJ\u003c/strong\u003e)\u003cstrong\u003e \u003c/strong\u003eUMAP plots showing the differential expression of indicated genes in control and IMQ samples.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eK-M\u003c/strong\u003e) Control or IMQ (day 5) skin samples were subjected to immunostaining of PRG4 (green), PDGFRA (blue) and DAPI (blue) in K, or SAA3 (red), PDGFRA (blue) and DAPI (white) in L, or TNC (green), KRT14 (blue), and DAPI (white) in M. Scale bar, 200 μm.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eN\u003c/strong\u003e)\u003cstrong\u003e \u003c/strong\u003eProposed model for the spatial locations of various dFB subpopulations in the IMQ treated skin. Dash line arrows mark the predicted differentiation trajectory of dFB clusters based on scRNAseq analyses (Fig.2G, S2E-F). Abbreviations: Epi, epidermis, AP, adipocyte progenitor; pAd, preadipocyte; Ad, adipocyte.\u003c/p\u003e","description":"","filename":"050124PSOanddWATmanuscriptmainfiguresPage2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4346630/v1/0c1cfa8bbca25aa76a2990d9.jpg"},{"id":56682542,"identity":"b3317154-7cba-40ea-b603-1b68e87fbc90","added_by":"auto","created_at":"2024-05-17 18:26:44","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2361007,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNeutrophils trigger the inflammatory response of dFBs through the IL1β-IL1R signaling axis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eA\u003c/strong\u003e) GO pathway analysis of the dFB_r3 pAd cluster showing top upregulated pathways after IMQ application\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eB\u003c/strong\u003e) Violin charts showing the expression of \u003cem\u003eIl1b\u003c/em\u003e and \u003cem\u003eIl1r1 \u003c/em\u003eacross various cell types from Ctrl and IMQ-treated skin.\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eC\u003c/strong\u003e) Immunostaining of IL1R1 (green), PDGFRA (red), PLIN1 (blue) and DAPI (white) on skin sections from IMQ-treated IL1r1-/- or WT mouse skin samples. IL1r1-/-skin was used as negative staining control for anti-IL1R1 antibody. Asterisks indicate non-specific IL1R1 signal on epidermal or hair follicle cells. Sc ale bar, 200 μm.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eD\u003c/strong\u003e) Volcano plots showing the differentially expressed genes in primary neonatal dFBs treated with IL1β.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eE-J\u003c/strong\u003e) Mouse back skin were injected with isotype (Ctrl) or anti-Ly6G antibodies to deplete neutrophils during IMQ-application (see schematic diagram in \u003cstrong\u003eE\u003c/strong\u003e). Presentation of the phenotype (\u003cstrong\u003eF\u003c/strong\u003e) and PASI score (\u003cstrong\u003eG\u003c/strong\u003e) of lesional skin. (\u003cstrong\u003eH\u003c/strong\u003e) Quantified bar graphs (from FACS plots shown in Figure S3E) showing the percentage of neutrophils (Ly6G\u003csup\u003e+\u003c/sup\u003eCD11B\u003csup\u003e+\u003c/sup\u003e) in total skin cells (n = 3/group). (\u003cstrong\u003eI\u003c/strong\u003e) qRT-PCR analysis of the mRNA expression of \u003cem\u003eIl1b\u003c/em\u003e,\u003cem\u003e Cxcl1\u003c/em\u003e, and \u003cem\u003eSaa3 \u003c/em\u003e(n=4/group). (\u003cstrong\u003eJ\u003c/strong\u003e) Immunostaining of SAA3 (red), PDGFRA (blue) and DAPI (white). Scale bar, 200 μm. (\u003cstrong\u003eK\u003c/strong\u003e) Quantified results of Fig. 3J showing the fluorescence intensity values (arbitrary units) of PDGFRA and SAA3 in the dWAT tissue. White dotted lines mark the boarders of dWAT layer. Scale bar, 200 μm.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eL-Q\u003c/strong\u003e) \u003cem\u003eIl1r1\u003c/em\u003e\u003csup\u003e\u003cem\u003e-/+\u003c/em\u003e\u003c/sup\u003e (HET) and \u003cem\u003eIl1r1\u003c/em\u003e\u003csup\u003e\u003cem\u003e-/-\u003c/em\u003e\u003c/sup\u003e\u003csup\u003e \u003c/sup\u003e(KO) mice were subjected to IMQ application, and skin samples were collected at day 5 for analysis. Representative skin-lesion pictures (\u003cstrong\u003eL\u003c/strong\u003e) and PASI scores (\u003cstrong\u003eM\u003c/strong\u003e) (n=4/group). (\u003cstrong\u003eN\u003c/strong\u003e) Quantified results showing the dWAT thickness (from H\u0026amp;E staining images in Figure S3J) (n=15/group). (\u003cstrong\u003eO\u003c/strong\u003e) Immunostaining of SAA3 (red), PDGFRA (blue) and DAPI (white). Scale bar, 200 μm. (\u003cstrong\u003eP\u003c/strong\u003e) Quantified result of Fig. 3O showing SAA3 protein levels in dWAT (n = 5/group). (\u003cstrong\u003eQ\u003c/strong\u003e) qRT-PCR analysis of \u003cem\u003eSaa3\u003c/em\u003e and \u003cem\u003eCxcl1\u003c/em\u003e (n = 3~5/group).\u003c/p\u003e\n\u003cp\u003eAll error bars indicate mean ± SEM; *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001, ****p \u0026lt; 0.0001.\u003c/p\u003e","description":"","filename":"050124PSOanddWATmanuscriptmainfiguresPage3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4346630/v1/9e6ede576408eba2c8a3f53b.jpg"},{"id":56683242,"identity":"019c2b9a-9aac-4443-92a8-6395e0a1f51e","added_by":"auto","created_at":"2024-05-17 18:34:44","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3256820,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNeutrophils and dFBs interact through the reciprocal IL1β-IL1R and CXCL1-CXCR2 signaling circuit\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eA\u003c/strong\u003e) Violin plots showing the expression of \u003cem\u003eCxcl1\u003c/em\u003e, \u003cem\u003eCxcl2\u003c/em\u003e and \u003cem\u003eCxcr2\u003c/em\u003e in various cell types from control (blue) and IMQ (red) skin.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eB\u003c/strong\u003e) Hierarchical plot showing the inferred Cxcl1-Cxcr2 signaling network.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eC\u003c/strong\u003e) Immunostaining of CXCL1 (green), PDGFRA (blue), and DAPI (white). Scale bar, 200 μm.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eD-G\u003c/strong\u003e) dFB conditioned medium (CM) was collected from IL1β-primed dFBs (dFB\u003csup\u003eIL1β\u003c/sup\u003e) then used to stimulate neutrophils (see schematic diagram in \u003cstrong\u003eD\u003c/strong\u003e, image created with bioRender.com). (\u003cstrong\u003eE-F\u003c/strong\u003e) Neutrophils treated with dFB\u003csup\u003eIL1β\u003c/sup\u003e-CM in the presence of anti-Cxcl1 antibody were subjected to qRT-PCR analysis of \u003cem\u003eIl1b\u003c/em\u003e and \u003cem\u003eCxcl2\u003c/em\u003e (n = 3/group). (\u003cstrong\u003eG\u003c/strong\u003e) Neutrophils treated with dFB\u003csup\u003eIL1β\u003c/sup\u003e-CM derived from \u003cem\u003eSaa3\u003c/em\u003e knockdown neonatal dFBs were subjected to qRT-PCR analysis of \u003cem\u003eNos2.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eH-I\u003c/strong\u003e) Schematic diagram (\u003cstrong\u003eH\u003c/strong\u003e) of neutrophils transmigration assay in response to dFB-CM (image created with bioRender.com). (\u003cstrong\u003ei\u003c/strong\u003e) Bar graphs showing quantified numbers of the transmigrated neutrophils (stained with LY6G, green) (n=10~20 areas/sample). Scale bar, 200 μm.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eJ-N\u003c/strong\u003e) Anti-CXCL1 antibody or rat IgG2A isotype control antibody was injected intravenously during IMQ-application, and skin biopsies were collected for analysis at day 4 p.t. (schematic diagram in \u003cstrong\u003eJ\u003c/strong\u003e). Representative images (\u003cstrong\u003eK\u003c/strong\u003e) and PASI score (\u003cstrong\u003eL\u003c/strong\u003e) of the lesional skin from each group. Scale bar, 0.5 cm. (\u003cstrong\u003eM\u003c/strong\u003e) Immunostaining of PLIN1 (red), LY6G (green), and DAPI (white). White dotted lines mark the boarders of the dWAT layer. Scale bar, 200 μm. (\u003cstrong\u003eN\u003c/strong\u003e) qRT-PCR analysis of the listed genes in nonlesional (NL) or lesional skin (LS) biopsies.\u003c/p\u003e\n\u003cp\u003eAll error bars indicate mean ± SEM. *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001, ****p \u0026lt; 0.0001.\u003c/p\u003e","description":"","filename":"050124PSOanddWATmanuscriptmainfiguresPage4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4346630/v1/2f23b24db0c63cecb6c9925a.jpg"},{"id":56682536,"identity":"420ba5c1-7088-480f-9c56-4e3147f17419","added_by":"auto","created_at":"2024-05-17 18:26:43","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":3003494,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProlonged skin inflammation prompts the differentiation of Preadipocytes to Adipocyte\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eA\u003c/strong\u003e) Pdgfra-ERT2cre;mTmG mice were i.p. injected daily with tamoxifen (TAM) during day 0~3 of IMQ application, and skin biopsies were collected at day 6 for immunostaining of FABP4 (blue/B), GFP (green/G), Tomato (Red/R), and DAPI (White). Zoom-in images showing different overlaid colors were shown on the right. Scale bar, 100 μm.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eB\u003c/strong\u003e) Neonatal dFBs treated with IL1β for 8 hours or 48 hours were subjected to qRT-PCR analysis of the mRNA expression levels of Pparg and Fabp4 (n=3/group).\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eC\u003c/strong\u003e) Heatmap showing the mRNA expression of indicated genes during the in vitro differentiation of subconfluent dFBs/AP, to pAds, then early adipocytes (eAd), and mature adipocytes (mAds).\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eD\u003c/strong\u003e) Heatmap showing the mRNA expression kinetics (based on qRT-PCR analysis) of listed genes in IMQ treated skin at the indicated time point (average of n=3).\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eE\u003c/strong\u003e) qRT-PCR analysis showing the mRNA expression kinetics of indicated genes during day 0~ 10 of IMQ application (n =3-6/ group).\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eF\u003c/strong\u003e) Representative immunofluorescent images of PPARγ (red) and DAPI (blue) in skin section from CTRL or IMQ-skin mice. Scale bars, 200 μm.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eG-K\u003c/strong\u003e) IMQ treated skin samples were subjected to single-nuclei RNA seqencing analysis (snRNA-seq). (\u003cstrong\u003eG\u003c/strong\u003e) tSNE plots showing the distribution of reclustered fibroblasts and adipocytes. (\u003cstrong\u003eH\u003c/strong\u003e) tSNE plots showing the expression of indicated genes (\u003cem\u003ePparg\u003c/em\u003ein red; \u003cem\u003eLpl \u003c/em\u003ein blue; both in yellow; none in gray). (\u003cstrong\u003eI\u003c/strong\u003e) Cell trajectory analysis of dFB and adipocyte clusters, and pseudotime (arbitrary units) is depicted from blue to red as indicated. (\u003cstrong\u003eJ\u003c/strong\u003e) Box plots showing the inflammatory or adipocyte (Ad) enrichment scores for each cell cluster. (\u003cstrong\u003eK\u003c/strong\u003e) Bubble plots showing the expression of indicated genes in the r1_pAd and r2_adipocyte clusters.\u003c/p\u003e","description":"","filename":"050124PSOanddWATmanuscriptmainfiguresPage5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4346630/v1/37c2962bea9e81d8fa72dc93.jpg"},{"id":56682538,"identity":"f8715a88-ea03-4ee2-8f43-88193a1eca5c","added_by":"auto","created_at":"2024-05-17 18:26:43","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1368366,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePPARγ-mediated preadipocyte differentiation is necessary for the resolution of skin neutrophilic inflammation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eA-F\u003c/strong\u003e) C57BL/6 mice (2 months old, male) were treated i.p. with DMSO (control) or BADGE during IMQ appilication (experimental scheme in \u003cstrong\u003eA\u003c/strong\u003e). Representative images (\u003cstrong\u003eB\u003c/strong\u003e) and PASI scores (\u003cstrong\u003eC\u003c/strong\u003e) of the lesional skin from each group. Representative H\u0026amp;E staining images (\u003cstrong\u003eD\u003c/strong\u003e) and immunofluorescent images of FABP4 (red), Ly6G (green), and DAPI (in blue) (\u003cstrong\u003eE\u003c/strong\u003e). Scale bars, 200 μm. (\u003cstrong\u003eF\u003c/strong\u003e) qRT-PCR analysis of the indicated genes (n =4/group).\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eG-K\u003c/strong\u003e) \u003cem\u003ePparg\u003c/em\u003e\u003csup\u003eflox/flox\u003c/sup\u003e\u003cem\u003e \u003c/em\u003eand \u003cem\u003ePdgfra-CreERT2; Pparg\u003c/em\u003e\u003csup\u003eflox/flox\u003c/sup\u003e (\u003cem\u003ePparg\u003c/em\u003e\u003csup\u003e\u003cem\u003e FB-iKO\u003c/em\u003e\u003c/sup\u003e) mice were administered \u003cem\u003ei.p.\u003c/em\u003e with TAM during IMQ application, and skin samples were collected at day 8 for analysis (schematic diagram in \u003cstrong\u003eG\u003c/strong\u003e). Representative images (\u003cstrong\u003eH\u003c/strong\u003e) and PASI scores (\u003cstrong\u003eI\u003c/strong\u003e) of the lesional skin from each group. (\u003cstrong\u003eJ\u003c/strong\u003e) Representative images showing bodipy (green), phalloidin (PHA), and DAPI (blue) staining. Scale bar, 200 μm. (\u003cstrong\u003eK\u003c/strong\u003e) qRT-PCR analysis of indicated genes (n=3-4/group) in the non-lesional and lesional skin samples.\u003c/p\u003e\n\u003cp\u003eAll error bars indicate mean ± SEM; *p \u0026lt; 0.05, **p \u0026lt; 0.01.\u003c/p\u003e","description":"","filename":"050124PSOanddWATmanuscriptmainfiguresPage6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4346630/v1/10f1bc7a48b50ea5c7874fd4.jpg"},{"id":56682541,"identity":"061b08e5-f699-4a2b-9892-c99231300265","added_by":"auto","created_at":"2024-05-17 18:26:44","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":2451749,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEarly adipocytes exhibit anti-inflammatory activity against myeloid cell activation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eA-F\u003c/strong\u003e) (\u003cstrong\u003eA\u003c/strong\u003e) Schematic diagram for the in vitro co-culture model between adipocytes and myeloid cells (image created with bioRender.com). Conditioned medium (CM) collected from undifferentiated (undif) dFB/pAd, differentiating early adipocytes (eAd), and mature adipocytes (mAd) were used to treated bone marrow-derived neutrophils or peritoneal macrophages in the presence of toll-like receptor ligands FSL or LPS as indicated. (\u003cstrong\u003eB\u003c/strong\u003e) ELISA analysis showing the secretion levels of CXCL2 by activated neutrophils (n=3/group). (\u003cstrong\u003eC-D\u003c/strong\u003e) qRT-PCR analysis showing the mRNA levels of \u003cem\u003eIl1b \u003c/em\u003eand \u003cem\u003eNos2 \u003c/em\u003ein activated macrophages (n=3/group).\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eE-J\u003c/strong\u003e) Blank medium or conditioned medium from eAd were injected intradermally during IMQ application, and skin biopsies were collected for analysis at day 6 p.t.. (\u003cstrong\u003eE\u003c/strong\u003e) Schematic diagram. Representative images (\u003cstrong\u003eF\u003c/strong\u003e) and PASI scores (\u003cstrong\u003eG\u003c/strong\u003e) of the lesional skin from each group (n=4/group). Scale bar, 0.5 cm. (\u003cstrong\u003eH\u003c/strong\u003e) qRT-PCR analysis of the listed genes in non-lesional and lesional skin samples (n=3/group). (\u003cstrong\u003eI\u003c/strong\u003e) H\u0026amp;E staining of the lesional skin sections. Black dotted lines mark the boarder between the dermis and dWAT layers. Scale bar, 200 μm. Immunostaining (\u003cstrong\u003eJ\u003c/strong\u003e) of Ki67 (red), LY6G (green) and DAPI (blue). White dotted lines mark the boarder of the dWAT layer. Scale bar, 200 μm.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eK\u003c/strong\u003e) qRT-PCR of macrophages treated with LPS in the presence of blank medium (BM) or eAd-CM, which were heated to 95℃ to inactivate protein (n=3/group).\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eL-M\u003c/strong\u003e) (\u003cstrong\u003eL\u003c/strong\u003e) Schematic diagram for the extraction of lipid and protein fractions from CM for functional assays. (\u003cstrong\u003eM\u003c/strong\u003e) qRT-PCR analysis of the expression of\u003cem\u003e Il1b\u003c/em\u003eand \u003cem\u003eCxcl2\u003c/em\u003e in macrophages treated with LPS and total, lipid, or protein fractions of eAd-CM (n=3~6/group).\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eN-S\u003c/strong\u003e) (\u003cstrong\u003eN)\u003c/strong\u003eSchematic diagram for topical application of eAd-lipid Lipids in the presence of Sponge \u003cem\u003eHaliclona sp. Spicules \u003c/em\u003e(SHS) during IMQ application.Representative images (\u003cstrong\u003eO\u003c/strong\u003e) and PASI score (\u003cstrong\u003eP\u003c/strong\u003e) of the lesional skin from each group (n=4~5/group). Scale bar, 0.5 cm. (\u003cstrong\u003eQ\u003c/strong\u003e) Immunostaining of Ki67 (red), LY6G (green) and DAPI (blue). White dotted lines mark the boarder of the dWAT layer. Scale bar, 200 μm. (\u003cstrong\u003eR\u003c/strong\u003e) Quantified result of Fig. 6Q showing the number of Ki67+ cells per mm in the skin epidermis. Scale bar, 200 μm. (\u003cstrong\u003eS\u003c/strong\u003e) qRT-PCR analysis of the listed genes in the non-lesional and lesional skin samples.\u003c/p\u003e\n\u003cp\u003eAll error bars indicate mean ± SEM. *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001, ****p \u0026lt; 0.0001.\u003c/p\u003e","description":"","filename":"050124PSOanddWATmanuscriptmainfiguresPage7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4346630/v1/fb37cc5a8fb6ee07332421eb.jpg"},{"id":56682540,"identity":"19432438-e248-4679-982d-76b9ffb52332","added_by":"auto","created_at":"2024-05-17 18:26:44","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":2353185,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePreadipocyte Signature and IL1 Pathway Enrichment Characterize Proinflammatory Fibroblasts in Human Psoriasis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eA-F\u003c/strong\u003e)\u003cstrong\u003e \u003c/strong\u003eScRNA-seq data of human psoriasis database (Reynolds et al., 2021). (\u003cstrong\u003eA\u003c/strong\u003e) Violin plots showing the expression of indicated marker genes in various cell types. (\u003cstrong\u003eB\u003c/strong\u003e) Monocle analysis showing the differentiation pseudotime values projected to tSNE plot. (\u003cstrong\u003eC\u003c/strong\u003e) Cell density pseudotemporal patterns of each dFB clusters. (\u003cstrong\u003eD\u003c/strong\u003e) Heatmap showing Spearman correlation between human psoriasis dFB clusters and mouse IMQ dFB clusters. (\u003cstrong\u003eE\u003c/strong\u003e) tSNE plot showing the distribution of preadipocytes or inflammatory signature scores. (\u003cstrong\u003eF\u003c/strong\u003e) GO pathway analysis showing the top enriched pathways in human dFB_r2 cells as shown in bubble diagram.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eJ\u003c/strong\u003e)\u003cstrong\u003e \u003c/strong\u003eBar graphs showing the expression (based on RNAseq FPKM values) of indicated genes in normal skin (NN), plaque psoriasis (PV) and generalized pustular psoriasis (GPP) skin samples.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eK\u003c/strong\u003e)\u003cstrong\u003e \u003c/strong\u003eCorrelation expression plots of indicated genes. Linear correlation analysis was performed by Pearson correlation coefficient method. The r value represents the correlation coefficent strength, and p value assesses the statistic significance of the correlation.\u003c/p\u003e\n\u003cp\u003eAll error bars indicate mean ± SEM. *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001, ****p \u0026lt; 0.0001.\u003c/p\u003e","description":"","filename":"050124PSOanddWATmanuscriptmainfiguresPage8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4346630/v1/5132d744bef0ab67234d03f0.jpg"},{"id":85274580,"identity":"56f8cdc2-7b9e-493d-b165-5e91966da1ea","added_by":"auto","created_at":"2025-06-24 07:07:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":23864391,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4346630/v1/d821bdf6-ebd2-4a73-9a07-47324dded4cb.pdf"},{"id":56682539,"identity":"31a0ad54-7203-4267-8e89-efde5b750a89","added_by":"auto","created_at":"2024-05-17 18:26:44","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":8293253,"visible":true,"origin":"","legend":"","description":"","filename":"050124SupplementalfilesCombined.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4346630/v1/10ba36c807e458544f93ca4a.pdf"}],"financialInterests":"(Not answered)","formattedTitle":"Dermal adipogenesis protects against neutrophilic skin inflammation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe skin, situated at the interface between the body and the environment, is continuously exposed to pathogens, toxins, allergens, and mechanical insults. Neutrophils, the most abundant circulating leukocytes in the body, are swiftly recruited to sites of infection and/or inflammation by chemotactic factors to eliminate pathogens and cellular debris\u003csup\u003e1,2\u003c/sup\u003e. However, prolonged activation and accumulation of neutrophils result in excessive production of reactive oxygen species (ROS), amplification of inflammatory responses, and initiation of autoimmunity, culminating in tissue damage and/or the onset of autoimmune skin conditions such as psoriasis and various skin ulcers\u003csup\u003e3\u0026ndash;7\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNeutrophil accumulation in the skin is considered a hallmark characteristic of the early stages of psoriasis\u003csup\u003e5\u003c/sup\u003e, a chronic inflammatory skin disease affecting 2\u0026ndash;3% of the global population. Psoriatic neutrophils play a significant role in maintaining the immune response in psoriasis\u003csup\u003e8\u003c/sup\u003e, and an excessive presence of neutrophils is a defining feature of generalized pustular psoriasis (GPP), an aggressive and potentially life-threatening form of the condition. GPP is characterized by the emergence of multiple sterile neutrophilic pustules over extensive areas of the skin\u003csup\u003e9,10\u003c/sup\u003e. Targeting and depleting neutrophils have shown promise in ameliorating clinical symptoms in patients with GPP who have not responded to conventional psoriasis therapies\u003csup\u003e11\u003c/sup\u003e, underscoring the pivotal role of neutrophils in driving GPP pathology. Neutrophil extracellular traps (NETs) promote the differentiation of T cells from human peripheral blood mononuclear cells into the IL17\u003csup\u003e+\u003c/sup\u003e (TH17) subtype\u003csup\u003e12\u003c/sup\u003e. Moreover, neutrophil exosomes can be internalized by keratinocytes, triggering the expression of proinflammatory molecules\u003csup\u003e13\u003c/sup\u003e. Additionally, matrix metallopeptidase 9 (MMP9) released from neutrophils enhances cutaneous vascular dilation and permeability, exacerbating psoriasis\u003csup\u003e14\u003c/sup\u003e. A comprehensive understanding of the innate immune mechanisms governing neutrophil infiltration and activation, as well as the resolution of neutrophilic inflammation in the skin, is urgently required to develop anti-inflammatory therapies targeting neutrophil-related skin inflammatory diseases.\u003c/p\u003e \u003cp\u003eThe skin is a multilayered organ comprising the epidermis, dermis, and highly plastic dermal white adipose tissue (dWAT), which rapidly expands or regresses in response to various stimuli\u003csup\u003e15\u0026ndash;19\u003c/sup\u003e. Upon deep skin bacterial infection, preadipocytes (pAds) rapidly expand and differentiate into early adipocytes that abundantly secrete the antimicrobial peptide protein CAMP to limit bacterial growth\u003csup\u003e18,19\u003c/sup\u003e, a response termed dermal reactive adipogenesis\u003csup\u003e20\u003c/sup\u003e. In contrast, mature adipocytes lose the ability to produce CAMP, which contributes to the increased susceptibility of obese individuals to skin bacterial infection\u003csup\u003e19\u003c/sup\u003e. Recent advances in single-cell RNA-seq have identified highly heterogeneous adipocyte-lineage cells, including committed preadipocytes and pluripotent adipocyte progenitors (AP) from the reticular dermis and/or hypodermal interstitium\u003csup\u003e15\u003c/sup\u003e. During skin development and wound healing, the commitment and differentiation of APs to pAd/adipocytes are controlled by the inflammatory factor IL1β released from myeloid cells, including neutrophils\u003csup\u003e15\u003c/sup\u003e, indicating that a cross-talk between adipocyte-lineage cells and neutrophils may exist and play a role in shaping skin inflammation during psoriasis pathogenesis.\u003c/p\u003e \u003cp\u003eIn this study, we aimed to investigate the roles of adipocyte-lineage cells, including adipogenic fibroblasts (preadipocytes) and adipocytes, in modulating neutrophilic inflammation in an animal model of psoriasis. Utilizing single-cell, single-nuclei, and multiple in vivo and in vitro co-culture functional models, we explored the cellular and molecular mechanism underlying the interactions between preadipocytes, adipocytes, and neutrophils. To assess the clinical relevance of our findings, we analyzed single-cell and bulk-sequencing databases derived from human psoriatic skin samples. These data uncover a previously unrecognized role of dermal adipocyte lineage cells in regulating neutrophilic inflammation during the pathogenesis of psoriasis.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cb\u003eDermal adipogenesis is dynamically coupled with the initiation and resolution of neutrophilic skin inflammation in the imiquimod-induced psoriasis mouse model\u003c/b\u003e \u003c/p\u003e \u003cp\u003eInfiltration of neutrophils is considered the hallmark of the onset of psoriatic inflammation\u003csup\u003e21\u003c/sup\u003e. Immunostaining of human skin samples showed that myeloperoxidase-positive (MPO\u003csup\u003e+\u003c/sup\u003e) neutrophils were found in close proximity to vimentin-positive (VIM\u003csup\u003e+\u003c/sup\u003e) fibroblasts in the dermis of patients with plaque psoriasis (PV) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Furthermore, the dermis from patients with generalized pustular psoriasis (GPP) exhibited an excessive accumulation of neutrophils around fibroblasts (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). These findings suggest that aberrant activation of dermal fibroblasts may contribute to the activation and accumulation of neutrophils, potentially driving the pathogenesis of psoriasis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo gain insight into the dermal mechanism of neutrophil activation, we utilized the imiquimod (IMQ)-induced psoriasis-like mouse model, wherein neutrophil infiltration plays a pivotal role in the pathogenesis of skin inflammation \u003csup\u003e13,22,23\u003c/sup\u003e. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB-C, daily application of IMQ led to the progression of skin erythema, thickening, and scaling continued steadily up to 6 days post-treatment (\u003cem\u003ep.t.\u003c/em\u003e), whereas these clinical manifestations began to resolve from 6\u0026thinsp;~\u0026thinsp;10 days \u003cem\u003ep.t.\u003c/em\u003e, indicating the development of self-tolerance to IMQ over prolonged exposure.\u003c/p\u003e \u003cp\u003eHistological analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC-D, S1A-C) revealed a rapid reduction of the dWAT layer by day 2 \u003cem\u003ep.t.\u003c/em\u003e, followed by a pronounced re-expansion of dWAT, where neutrophils characterized by their distinctive multi-lobulated nuclei\u003csup\u003e24\u003c/sup\u003e were detected at day 3 \u003cem\u003ep.t.\u003c/em\u003e; re-growth of mature adipocytes occurred from day 6 to 10 \u003cem\u003ep.t.\u003c/em\u003e, coinciding with inflammation resolution. Analysis of neutrophils, marked by high level of Ly6G and CD11B expression\u003csup\u003e25,26\u003c/sup\u003e (Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eD-F), confirmed that neutrophil infiltration peaked between 3 and 6 \u003cem\u003ep.t.\u003c/em\u003e. Immunostaining to ascertain the spatial relationship between dWAT cells and neutrophils found that FABP4\u003csup\u003e+\u003c/sup\u003e adipocytes were rapidly lost by 3 \u003cem\u003ep.t.\u003c/em\u003e, and concurrently Ly6G\u003csup\u003e+\u003c/sup\u003e neutrophils and PDGFRA\u003csup\u003e+\u003c/sup\u003e fibroblasts specifically co-populated the dWAT layer, with a peak in their presence observed at day \u003cem\u003e3 p.t.\u003c/em\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF-G). Subsequently, from day 6 to 10 \u003cem\u003ep.t.\u003c/em\u003e, there was a repopulation of FABP4\u003csup\u003e+\u003c/sup\u003e adipocytes within the dWAT, coinciding with a clearance of neutrophils from the skin (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF-G).\u003c/p\u003e \u003cp\u003eLipid staining analyses, conducted to evaluate changes of lipogenesis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eH, Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eG), indicated a reduction in lipid-laden adipocyte size on day 3, with a subsequent re-expansion by day 6 p.t.. Quantitative analysis of CAV1\u003csup\u003e+\u003c/sup\u003ePLIN1\u003csup\u003e+\u003c/sup\u003e adipocytes revealed a transient decrease in the number of large, mature adipocytes (\u0026gt;\u0026thinsp;1000 \u0026micro;m\u003csup\u003e2\u003c/sup\u003e) on day 3 p.t., accompanied by a rise in the number of small adipocytes (\u0026lt;\u0026thinsp;500 \u0026micro;m\u003csup\u003e2\u003c/sup\u003e) observed on both days 3 and 6 p.t. (Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eH-I, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eI). Moreover, there was a notable regeneration of PDGFRA\u003csup\u003e+\u003c/sup\u003e fibroblasts within the dWAT region (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eJ). Additionally, fibroblasts derived from IMQ-treated skin samples (p.t. day 3 or 6) exhibited an enhanced adipogenic potential in vitro (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eJ-K). Collectively, these findings depict a two-step adipogenic response triggered by the IMQ application. In the early phase of inflammation progression, dWAT is repopulated with PDGFRA\u003csup\u003e+\u003c/sup\u003e preadipocytes (pAds), along with neutrophils. Subsequently, a re-expansion of lipid-ladened adipocytes coincides with the regression of neutrophils as the inflammation enters its resolution phase.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDefining the immune response of\u003c/b\u003e \u003cb\u003ePdgfra\u003c/b\u003e\u003csup\u003e\u003cb\u003e+\u003c/b\u003e\u003c/sup\u003e \u003cb\u003edermal fibroblasts by scRNAseq\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTo elucidate the cell type-specific immune responses underlying IMQ-induced skin inflammation, we performed single-cell RNA sequencing (scRNA-seq) analysis on both control and IMQ-treated skin samples. The analysis led to the identification of 27 distinct cell clusters, which were categorized into various cell types such as dFBs, keratinocytes (KC), neutrophils (NEU), macrophages (MAC), and T cells, based on the expression of established marker genes (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA-B, Fig. S2A-C). Through differential gene expression analysis\u003csup\u003e27\u003c/sup\u003e, we identified the most differentially upregulated genes across these cell types. Notably, in dermal fibroblasts, \u003cem\u003eSaa3\u003c/em\u003e and \u003cem\u003ePrg4\u003c/em\u003e were markedly upregulated; in keratinocytes, \u003cem\u003eS100a8\u003c/em\u003e and \u003cem\u003eKrt6a\u003c/em\u003e were the top upregulated genes; T cells exhibited heightened expression of \u003cem\u003eIl22\u003c/em\u003e and \u003cem\u003eIl17a/f\u003c/em\u003e; neutrophils displayed increased expression of \u003cem\u003eCxcl2\u003c/em\u003e; and macrophages exhibited elevated expression of \u003cem\u003eChil3\u003c/em\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC-D).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo further characterize the immune response of fibroblasts, \u003cem\u003ePdgfra\u003c/em\u003e\u003csup\u003e+\u003c/sup\u003e dFBs were classified into seven sub-clusters (r1\u0026thinsp;~\u0026thinsp;r7), denoted as reticular (RET), papillary (PAP), and follicular dFBs, as well as various adipocyte-lineage cell clusters, including adipose regulatory cells (Areg), adipocyte progenitors (AP), and pAds, based on the expression of established dFB marker genes (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE, S2D)\u003csup\u003e15\u003c/sup\u003e. Among all dFB sub-clusters, application of IMQ notably increased the relative abundance of adipocyte-lineage cell clusters (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF). Multiple independent cellular differentiation trajectory analyses, including Monocle trajectory analysis, CytoTRACE, and RNA velocity, consistently predicted that dFB_r2 APs were differentiating into dFB_r3 pAds (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eG, S2E-F). Furthermore, both dFB_r2 and r3 cells showed a significant enrichment of preadipocyte or inflammatory gene signatures after IMQ treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eH-I, S2G-H), suggesting that IMQ application may promote the accumulation of proinflammatory AP/pAds in the skin. Following IMQ application, \u003cem\u003eSaa3, Prg4, Lcn2, Cxcl1\u003c/em\u003e, and \u003cem\u003eCxcl12\u003c/em\u003e were identified as the most prominently upregulated genes in dFB_r2 and/or r3 cells, while \u003cem\u003eTnc\u003c/em\u003e was uniquely upregulated in dFB_r6 PAP/follicular cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eJ, S2I-J). Notably, \u003cem\u003ePrg4\u003c/em\u003e and \u003cem\u003eFabp4\u003c/em\u003e were co-induced in the dFB_r2 cells, whereas \u003cem\u003eSaa3\u003c/em\u003e showed higher levels of induction in r3, r1, and r6 cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eJ, S2I-J). This differential expression pattern of Prg4 and Saa3 may reflect distinct activation states of pAds.\u003c/p\u003e \u003cp\u003eImmunostaining analysis confirmed the presence of PRG4\u003csup\u003e+\u003c/sup\u003e cells, which were exclusively localized to the dWAT layer, and these cells co-expressed PDGFRA and PLIN1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eK, S2K), indicating that PRG4 marks activated pAds that are undergoing differentiation into PLIN1\u003csup\u003e+\u003c/sup\u003e adipocytes. Additionally, SAA3\u003csup\u003e+\u003c/sup\u003e cells, which also co-expressed PDGFRA, were abundantly detected not only within the dWAT but also in the reticular dermis and at the dermal-epidermal junction (DEJ) region in skin treated with IMQ (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eL). Within the dWAT, SAA3\u003csup\u003e+\u003c/sup\u003e cells co-expressed medium-to-low levels of PRG4 (Fig. S2L-M). In contrast, TNC expression was predominantly induced by IMQ in the DEJ and follicular regions, but not in the dWAT (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eM). These immunostaining findings align with the gene expression pattern observed in the scRNAseq results (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eJ and S2J).\u003c/p\u003e \u003cp\u003eTogether, our findings suggest that IMQ application triggers a cascade of events that promote dermal adipogenesis. Specifically, \u003cem\u003eAnxa3\u003c/em\u003e\u003csup\u003e\u003cem\u003e+\u003c/em\u003e\u003c/sup\u003e APs appear to be primed to differentiate into proinflammatory \u003cem\u003eSaa3\u003c/em\u003e\u003csup\u003e\u003cem\u003e+\u003c/em\u003e\u003c/sup\u003e pAds or \u003cem\u003ePrg4\u003c/em\u003e\u003csup\u003e\u003cem\u003e+\u003c/em\u003e\u003c/sup\u003e pAds that have the potential to differentiate into \u003cem\u003eFabp4\u003c/em\u003e\u003csup\u003e\u003cem\u003e+\u003c/em\u003e\u003c/sup\u003e adipocytes. Additionally, \u003cem\u003eSaa3\u003c/em\u003e\u003csup\u003e\u003cem\u003e+\u003c/em\u003e\u003c/sup\u003e pAds may further differentiate into \u003cem\u003eSaa3\u003c/em\u003e\u003csup\u003e\u003cem\u003e+\u003c/em\u003e\u003c/sup\u003e\u003cem\u003eTnc\u003c/em\u003e\u003csup\u003e\u003cem\u003e+\u003c/em\u003e\u003c/sup\u003e dFBs within the DEJ region (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eN). It is important to note that further research is required to validate these proposed differentiation trajectories of adipocyte-lineage cells during psoriasis pathogenesis.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eNeutrophils trigger the inflammatory response of dFBs through the IL1β-IL1R signaling axis\u003c/h2\u003e \u003cp\u003eGO pathway analysis identified IL1 and neutrophil chemotaxis as the most significantly upregulated pathways in dFB_r3 pAds following IMQ application (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Cell-chat analysis of the IL1b-IL1r1 signaling network pinpointed neutrophils as the primary source of the IL1 ligand, acting on IL1r expressed on dFB clusters (Fig. S3A). Violin plots further illustrated that neutrophils expressed the highest level of \u003cem\u003eIl1b\u003c/em\u003e among all major cell types examined, whereas dFBs expressed the highest level of \u003cem\u003eIl1r1\u003c/em\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Immunostaining data revealed that IMQ application specifically induced IL1R1 expression in PDGFRA\u003csup\u003e+\u003c/sup\u003e dFBs within dWAT (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC, S4B). In vitro study also identified \u003cem\u003eSaa3\u003c/em\u003e and \u003cem\u003eCxcl1\u003c/em\u003e as the most prominent inducible genes by IL1β in primary neonatal dFBs (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD), which are composed of over 90% PDGFRA\u003csup\u003e+\u003c/sup\u003eLy6A\u003csup\u003e+\u003c/sup\u003eTHY1\u003csup\u003e+\u003c/sup\u003e APs/pAds (Fig. S3C). These findings imply that IL1β, released from neutrophils, may play a crucial role in activating dFBs during psoriasis pathogenesis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo validate the role of neutrophils in activating dFB, we systemically depleted neutrophils via intravenous injection of the Ly6G antibody (Fig. S3D-E). This depletion significantly reduced neutrophil infiltration into the skin and suppressed the development of psoriatic phenotypes induced by IMQ (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE-H, S3F). Moreover, \u003cem\u003eIL1b\u003c/em\u003e expression was substantially reduced upon neutrophil depletion (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eI), supporting the idea that neutrophils are a primary source of IL1β in IMQ-treated skin. Consequently, the IMQ-induced mRNA expression of \u003cem\u003eSaa3\u003c/em\u003e and \u003cem\u003eCxcl1\u003c/em\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eI), as well as protein expression of SAA3 in PDGFRA\u003csup\u003e+\u003c/sup\u003e dFBs (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eJ-K) were significantly diminished upon neutrophil depletion.\u003c/p\u003e \u003cp\u003eTo further validate the role of IL1 signaling in dFB activation, \u003cem\u003eIL1r1\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u0026minus;/\u0026minus;\u003c/em\u003e\u003c/sup\u003e (KO) and wildtype (WT) littermate mice were subjected to IMQ-application (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eL, S3I). IL1r1 deficiency not only inhibited the progression of the psoriatic phenotype (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eL-M), but also blocked IMQ-induced dWAT expansion (Fig. S3J, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eN), SAA3 protein expression in PDGFRA\u003csup\u003e+\u003c/sup\u003e dFBs (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eO-P, S3K), and mRNA expression of \u003cem\u003eSaa3\u003c/em\u003e and \u003cem\u003eCxcl1\u003c/em\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eQ). Collectively, these results underscore the critical function of neutrophils in the immune activation of pAds via the IL1β-IL1R1 signaling pathway during the progression of IMQ-induced skin inflammation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eNeutrophils and dFBs engage in a bidirectional IL1β-IL1R and CXCL1-CXCR2 signaling circuit\u003c/h2\u003e \u003cp\u003eWe identified \u003cem\u003eCxcl1\u003c/em\u003e, a pivotal neutrophil chemotactic gene\u003csup\u003e28,29\u003c/sup\u003e, and \u003cem\u003eSaa3\u003c/em\u003e as the most highly expressed inflammatory genes inducible by IL1β in dFBs (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD). This prompted us to investigated the role of dFB-derived CXCL1 and/or SAA3 in driving neutrophil activation. scRNA-seq analysis showed that dFBs were the primary source of \u003cem\u003eCxcl1\u003c/em\u003e, acting on \u003cem\u003eCxcr2\u003c/em\u003e expressed by neutrophils, which reciprocally expressed \u003cem\u003eCxcl2\u003c/em\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA-B). Immunostaining confirmed that CXCL1 was predominantly expressed in PDGFRA\u003csup\u003e+\u003c/sup\u003e dFBs located in the dWAT following IMQ treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC, S4A).\u003c/p\u003e \u003cp\u003eTo further explore the cellular interactions between dFBs and neutrophils, we developed an in vitro co-culture system, in which conditioned medium was collected from IL1β-primed or control dFB (dFB\u003csup\u003eIL1β\u003c/sup\u003e-CM or dFB\u003csup\u003ectrl\u003c/sup\u003e-CM) to assess its effect on neutrophils (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eD). Our findings revealed that dFB\u003csup\u003eIL1β\u003c/sup\u003e-CM significantly upregulated the expression of \u003cem\u003eIl1b, Cxcl2, and Nos2\u003c/em\u003e in neutrophils (Fig. S4B). Notably, the addition of an anti-CXCL1 antibody reduced the induction of \u003cem\u003eIl1b\u003c/em\u003e and \u003cem\u003eCxcl2\u003c/em\u003e, though not \u003cem\u003eNos2\u003c/em\u003e, in neutrophils (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eE-F, S4C). In contrast, when dFB\u003csup\u003eIL1β\u003c/sup\u003e-CM was obtained from \u003cem\u003eSaa3\u003c/em\u003e knockdown dFBs, it led to a decrease in \u003cem\u003eNos2\u003c/em\u003e expression with no significant effect on Il1b or Cxcl2 \u003cem\u003eNos2\u003c/em\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eG, Fig. S4F-G).\u003c/p\u003e \u003cp\u003eFurthermore, dFB\u003csup\u003eIL1β\u003c/sup\u003e-CM was found to enhance neutrophil migratory activity in a transwell assay, and this effect was significantly attenuated by the anti-CXCL1 antibody (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eH-I, S4H). In contrast, primary keratinocytes, while responsive to IL17A with an inflammatory response, did not show induced expression of \u003cem\u003eIl1b\u003c/em\u003e, \u003cem\u003eCxcl1\u003c/em\u003e, or other keratinocyte-specific inflammatory genes following treatment with either IL1β nor dFB\u003csup\u003eIL1β\u003c/sup\u003e-CM (Fig. S4I-L). These findings suggest that the CXCL1-IL1β signaling circuit is specific to the interaction between dFBs and neutrophils, rather than with keratinocytes.\u003c/p\u003e \u003cp\u003eIn vivo, the administration of an anti-CXCL1 antibody concurrently with IMQ treatment in mice substantially alleviated the manifestation of IMQ-induced psoriatic phenotypes (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eJ-L), reduced the recruitment of Ly6G\u003csup\u003e+\u003c/sup\u003e neutrophils to dWAT (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eM), and diminished the expression of inflammatory genes associated with neutrophils or dFBs (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eN, S4M). These results collectively indicate that IL1β-activated pAds can augment neutrophil chemotaxis and activation through the secretion of CXCL1 and/or SAA3, contributing to the establishment of a self-perpetuating inflammatory response in in the skin dermis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eProlonged skin inflammation prompts the differentiation of Preadipocytes to Adipocyte\u003c/h2\u003e \u003cp\u003eWe next explored the mechanisms underlying the resolution of inflammation during extended imiquimod (IMQ) treatment. First, to determine whether \u003cem\u003ePdgfra\u003c/em\u003e\u003csup\u003e+\u003c/sup\u003e pAds can differentiate into adipocytes during the resolution phase of IMQ-induced skin inflammation, we induced CRE activity in \u003cem\u003ePdgfra\u003c/em\u003e-ERT2cre;mTmG mice by tamoxifen application during the initial days of IMQ application to label Pdgfra\u003csup\u003e+\u003c/sup\u003e dFBs with GFP (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). At day 6 p.t., we observed co-expression of GFP and FABP4 in the dWAT of IMQ-treated skin (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA), supporting the differentiation of PDGFRA\u003csup\u003e+\u003c/sup\u003e pAd into FABP4\u003csup\u003e+\u003c/sup\u003e adipocytes.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBuilding upon our previous work that IL1R signaling activation in dFBs triggers a dermal adipogenesis response crucial for during skin development and wound regeneration\u003csup\u003e15\u003c/sup\u003e, we have now observed that while brief IL1β exposure induced an immediate inflammatory response in dFBs, extended treatment significantly upregulated \u003cem\u003ePparg\u003c/em\u003e, the key transcription factor driving adipogenesis\u003csup\u003e\u003cem\u003e30\u003c/em\u003e\u003c/sup\u003e, along with other adipocyte-related genes (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB, S5A). Analysis of the transcriptomic changes during the in vitro adipogenesis process from dFBs/APs to adipocytes revealed a distinct sequence of molecular events. This included the commitment of \u003cem\u003eAnxa3\u003c/em\u003e\u003csup\u003e+\u003c/sup\u003e\u003cem\u003eThy1\u003c/em\u003e\u003csup\u003e\u003cem\u003ehi\u003c/em\u003e\u003c/sup\u003e dFBs to \u003cem\u003ePdgfra\u003c/em\u003e\u003csup\u003e\u003cem\u003ehi\u003c/em\u003e\u003c/sup\u003e\u003cem\u003eLy6a\u003c/em\u003e\u003csup\u003e\u003cem\u003ehi\u003c/em\u003e\u003c/sup\u003e pAds post-confluency, followed by differentiation into \u003cem\u003eCamp\u003c/em\u003e\u003csup\u003e\u003cem\u003e+\u003c/em\u003e\u003c/sup\u003e early adipocytes (eAd), and ultimately to \u003cem\u003ePparg\u003c/em\u003e\u003csup\u003e\u003cem\u003ehi\u003c/em\u003e\u003c/sup\u003e mature adipocytes (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eC). During this process, there was a rapid decline in the expression of IL1 pathway-related genes, \u003cem\u003eIl1r1\u003c/em\u003e and \u003cem\u003eCxcl1\u003c/em\u003e, and a transient expression of \u003cem\u003ePrg4\u003c/em\u003e by differentiating pAds (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003eIn vivo IMQ application mirrored these in vitro changes, showing an upregulation of \u003cem\u003ePrg4\u003c/em\u003e, identified as a marker for differentiating pAds, which preceded the induction of \u003cem\u003eCamp, Pparg\u003c/em\u003e, and other adipocyte-related genes between days 6 and 10 of IMQ application. Concurrently, there was a significant suppression of inflammatory genes, including \u003cem\u003eCxcl1\u003c/em\u003e, \u003cem\u003eSaa3\u003c/em\u003e, \u003cem\u003eIl1b\u003c/em\u003e, and \u003cem\u003eCxcl2\u003c/em\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eD-E, S5B-C). Immunostaining confirmed robust PPARγ induction in dermal white adipose tissue (dWAT) 6 days post-IMQ application (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eF). These findings suggest that a PPARγ-dependent adipocyte differentiation program is a critical component of the resolution phase of skin inflammation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eCharacterization of the immune response of Adipocytes by single-nuclei RNA sequencing\u003c/h2\u003e \u003cp\u003eTo maximally captured adipocytes, which are largely lost through enzymatic digestion in scRNA-seq\u003csup\u003e31\u003c/sup\u003e, we next performed single-nuclei RNA sequencing (Sn-RNAseq) of IMQ-treated skin samples. Sn-RNAseq identified a distinct cluster of \u003cem\u003ePparg\u003c/em\u003e\u003csup\u003e\u003cem\u003e+\u003c/em\u003e\u003c/sup\u003e adipocyte, representing 5% of the total cells (Fig. S5D-F). Further reclustering of fibroblast and adipocyte clusters delineated six sub-clusters (r0\u0026ndash;r5), including \u003cem\u003ePparg\u003c/em\u003e\u003csup\u003e\u003cem\u003ehi\u003c/em\u003e\u003c/sup\u003e\u003cem\u003eLpl\u003c/em\u003e\u003csup\u003e\u003cem\u003e+\u003c/em\u003e\u003c/sup\u003e\u003cem\u003eAdipoq\u003c/em\u003e\u003csup\u003e\u003cem\u003e+\u003c/em\u003e\u003c/sup\u003e adipocytes (r2), \u003cem\u003eLpl\u003c/em\u003e\u003csup\u003e\u003cem\u003e+\u003c/em\u003e\u003c/sup\u003e\u003cem\u003ePparg\u003c/em\u003e\u003csup\u003e\u003cem\u003elo\u0026minus;med\u003c/em\u003e\u003c/sup\u003e preadipocytes (r1), and various other dermal fibroblast clusters (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eG-H, S5G). Pseudotime analysis predicted the differentiation trajectory from r1_pAds to r2_adipocytes (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eI, S5H). Notably, r1_pAds exhibited the highest inflammatory scores and expressed high levels of \u003cem\u003eCxcl1\u003c/em\u003e and \u003cem\u003eSaa3\u003c/em\u003e, whereas r2_adipocytes showed the lowest inflammatory scores and expressed genes associated with adipogenesis (\u003cem\u003eCamp, Adipoq\u003c/em\u003e, and \u003cem\u003eFabp4\u003c/em\u003e) but not inflammatory genes (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eJ-K), suggesting that the inflammatory response is suppressed in differentiating adipocytes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePPARγ-mediated preadipocyte differentiation is necessary for the resolution of skin inflammation\u003c/h2\u003e \u003cp\u003eTo determine the role of PPARγ in mediating neutrophil clearance, we administered BADGE, a selective pharmacological inhibitor of PPARγ\u003csup\u003e19,32,33\u003c/sup\u003e, via intraperitoneal injection during IMQ application (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA). BADGE treatment led to an exacerbation of the psoriatic phenotype (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eB-C), inhibited the formation of FABP4\u003csup\u003e+\u003c/sup\u003e adipocytes in dWAT, and resulted in increased neutrophil infiltration and upregulation of neutrophil-associated inflammatory genes (\u003cem\u003eIl1b\u003c/em\u003e and \u003cem\u003eCxcl2\u003c/em\u003e) in IMQ-treated skin (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eD-F, S6A-B).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo block adipogenesis by deleting PPARγ in PDGFRA\u003csup\u003e+\u003c/sup\u003e pAds, we next generated tamoxifen (TAM)-inducible fibroblast-specific \u003cem\u003ePparg\u003c/em\u003e knockout mice, termed \u003cem\u003ePparg\u003c/em\u003e\u003csup\u003e\u003cem\u003eFB\u0026minus;iKO\u003c/em\u003e\u003c/sup\u003e, by crossing \u003cem\u003ePparg\u003c/em\u003e\u003csup\u003eflox/flox\u003c/sup\u003e mice with \u003cem\u003ePdgfra\u003c/em\u003e-cre/\u003cem\u003eERT\u003c/em\u003e mice (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eG). TAM application to \u003cem\u003ePparg\u003c/em\u003e\u003csup\u003e\u003cem\u003eFB\u0026minus;iKO\u003c/em\u003e\u003c/sup\u003e mice during IMQ-application specifically ablated the expression of \u003cem\u003ePPARγ\u003c/em\u003e in dWAT (Fig. S6C), leading to an exacerbation of psoriatic clinical phenotypes (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eH-I), inhibition of adipogenesis (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eJ, S6D) and \u003cem\u003eCamp\u003c/em\u003e expression (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eK), and increased expression of inflammatory genes (\u003cem\u003eCxcl2, IL1b, Nos2\u003c/em\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eK, S6E). These results highlight the critical role of PPARγ in preadipocyte differentiation and the resolution of neutrophilic skin inflammation during topical IMQ application.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eEarly adipocytes exhibit anti-inflammatory effects against myeloid cell activation\u003c/h2\u003e \u003cp\u003eWe next investigated the therapeutic potential of adipocytes in countering inflammation-medidated by myeloid cells, including neutrophils and macrophages. Conditioned medium (CM) was collected from three stages of adipocyte differentiation: undifferentiated (undif) dFB/pAd, early adipocytes (eAd) secreting CAMP, and mature adipocytes (mAd) with elevated FABP4 secretion (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eA). These CM samples were then used to treat neutrophils or peritoneal macrophages activated by FSL or LPS (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eA and Fig. S7A). Notably, CM from eAd, but not undif or mAd, significantly reduced the expression of proinflammation genes \u003cem\u003eCxcl2, IL1b\u003c/em\u003e, and \u003cem\u003eNos2\u003c/em\u003e in activated neutrophils and/or macrophages (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eB-D, S7B), and induced anti-inflammatory M2-macrophage-associated genes, such as \u003cem\u003eChil3\u003c/em\u003e and \u003cem\u003eCd163\u003c/em\u003e\u003csup\u003e\u003cem\u003e34\u003c/em\u003e\u003c/sup\u003e, in activated macrophages (Fig. S7C-D).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSubsequently, we explored the in vivo therapeutic effects of eAd-CM against IMQ-induced skin inflammation. eAd-CM \u003cem\u003ei.d.\u003c/em\u003e injections substantially alleviated the development of psoriatic phenotypes (Fig. S7E-G), reduced the expression of inflammatory genes (Fig. S7H), and decreased infiltration of Ly6G\u003csup\u003e+\u003c/sup\u003e neutrophils in dWAT (Fig. S7I-J) in IMQ-treated skin. Moreover, eAd-CM suppressed IMQ-induced epidermal hyperplasia and the presence of Ki67\u003csup\u003e+\u003c/sup\u003e proliferative epidermal cells (Fig. S7J-K), and inhibited the IMQ-mediated induction of \u003cem\u003eKrt6a, Defb14, and Il17a\u003c/em\u003e (Fig. S7H). Hence, eAd-CM\u0026rsquo;s inhibitory effect on epidermal cell activation is likely due to its suppressive effect on myeloid cell activation.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEarly adipocyte-derived lipids are anti-inflammatory\u003c/h3\u003e\n\u003cp\u003eWe observed that the anti-inflammatory substances in eAd-CM were heat-stable (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eE, S7L-M), suggesting they are not protein-based. In addition, only the lipid fraction, but not the protein fraction of eAd-CM, exhibited inhibitory effects against LPS-induced \u003cem\u003eIl1b, Cxcl2\u003c/em\u003e, and \u003cem\u003eNos2\u003c/em\u003e expression (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eF-G, S7N), demonstrating that the anti-inflammatory substances in eAd-CM are lipids. To develop a topical approach to deliver eAd_lipids, we utilized \u003cem\u003eHaliclona sp. spicules\u003c/em\u003e (SHS), microneedles derived from marine sponges, facilitating skin penetration of therapeutics even nanoparticles by overcoming barriers and creating nano-pores across the skin epithelium\u003csup\u003e35,36\u003c/sup\u003e. Topical application of lipids from eAd, in combination with SHS, effectively prevented the onset of IMQ-induced psoriatic features (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eH-J), blocked the infiltration of Ly6G\u003csup\u003e+\u003c/sup\u003e neutrophils (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eK), and reduced the number of epidermal Ki67\u003csup\u003e+\u003c/sup\u003e cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eK-L). Furthermore, it suppressed pro-inflammatory gene expression and restored the expression of claudin genes important for epidermal tight junctions (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eM, S7O).\u003c/p\u003e \u003cp\u003eThese results underscore the role of early adipocytes in secreting lipids with anti-inflammatory properties to attenuate myeloid cell activation, thereby aiding in the resolution of inflammation during IMQ application.\u003c/p\u003e\n\u003ch3\u003ePreadipocyte Signature and IL1 Pathway Enrichment Characterize Proinflammatory Fibroblasts in Human Psoriasis\u003c/h3\u003e\n\u003cp\u003eNext, we sought to establish the relevance of our mouse findings to human psoriasis by reanalyzing single-cell RNA sequencing (sc-RNA-seq) data from patients with psoriasis and healthy controls\u003csup\u003e37\u003c/sup\u003e. Aligning with mouse data, PDGFRA\u003csup\u003e+\u003c/sup\u003e dFBs were identified as the main producers of \u003cem\u003eIL1R1, CXCL1\u003c/em\u003e, and \u003cem\u003ePRG4\u003c/em\u003e, with myeloid cells predominantly expressing \u003cem\u003eIL1B\u003c/em\u003e in psoriatic lesions (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eA). Reclustering of PDGFRA\u003csup\u003e+\u003c/sup\u003e dFBs resulted in nine dFB subclusters (r0\u0026ndash;r8), and pseudotime analysis predicted that r1, r2, and r7 clusters were in the terminal state of cellular differentiation (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eB-C, S8A). Notably, correlation analysis revealed that the human r1 and r2 dFB clusters were closely related to the murine IMQ-induced dFB_r3 cluster, which represents the pro-inflammatory pAds (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eD). Additionally, dFB_r2 cells exhibited enrichment in pAd and inflammatory gene-set signatures (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eE).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGene Ontology (GO) analysis identified pathways, including responses to IL1, WNT, and TGFβ, as the top enriched pathways associated with dFB_r2 cells in human psoriasis (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eF). Given our previous findings that TGFβ and WNT are key inhibitors of dermal adipogenesis\u003csup\u003e15,18\u003c/sup\u003e, their overactivation may impede the transition of pro-inflammatory pAds into anti-inflammatory adipocytes, thereby potentially exacerbating dermal inflammation.\u003c/p\u003e \u003cp\u003eTo gain insight into the increased neutrophil infiltration in generalized pustular psoriasis (GPP) compared to plaque psoriasis (PV), we analyzed transcriptomic data from normal, PV, and GPP human skin samples (GSE79704)\u003csup\u003e38\u003c/sup\u003e. We found that GPP samples expressed higher levels of \u003cem\u003eIL1B, CXCL1\u003c/em\u003e, and key adipogenesis inhibitor genes \u003cem\u003eWNT3 and TGFB1\u003c/em\u003e, compared to normal and/or PV samples. In contrast, genes related to adipogenesis, including \u003cem\u003ePPARG, PRG4, CEBPB\u003c/em\u003e, and \u003cem\u003eFABP4\u003c/em\u003e, were downregulated in GPP samples (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eG, S8B). Furthermore, correlation analyses showed that \u003cem\u003eIL1B\u003c/em\u003e expression positively correlated with \u003cem\u003eCXCL1\u003c/em\u003e and negatively with \u003cem\u003ePPARG\u003c/em\u003e and \u003cem\u003ePRG4\u003c/em\u003e, while \u003cem\u003ePPARG\u003c/em\u003e and \u003cem\u003ePRG4\u003c/em\u003e exhibited a positive correlation (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eH, S8C).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs an emerging component of the skin's immune barrier, dWAT undergoes substantial expansion and contraction during infection and/or wound healing, thereby contributing to innate immune antimicrobial defense and skin regeneration\u003csup\u003e15,16,18,19\u003c/sup\u003e. However, the function of dWAT in shaping the skin immune response under inflammatory conditions remains largely unexplored. In this study, we observed a rapid expansion of dWAT alongside the proliferation of PDGFRA\u003csup\u003e+\u003c/sup\u003e preadipocytes, which secrete CXCL1 to chemoattract CXCR2\u003csup\u003e+\u003c/sup\u003e neutrophils. The neutrophils, in turn, release IL1β, which further activates pAds through IL1R. These interactions create a self-sustaining inflammatory loop within the dermis. Intriguingly, sustained activation of IL1R signaling in pAds leads to PPARγ-dependent adipogenesis, resulting in the formation of early adipocytes. These emerging adipocytes produce anti-inflammatory lipids that counteract neutrophilic inflammation. Notably, targeted inhibition of PPARγ, through either pharmacological or genetic approaches, prevents the formation of early adipocytes and impedes the resolution of inflammation. These findings elucidate a previous unrecognized mechanism by which resident cells develop self-tolerance to neutrophilic skin inflammation, involving the conversion of proinflammatory fibroblasts into anti-inflammatory adipocytes.\u003c/p\u003e \u003cp\u003eOur study underscores the dynamic immunoregulatory function of dermal white adipose tissue (dWAT) in the pathogenesis of neutrophilic skin inflammation, particularly in the imiquimod (IMQ)-induced model, the most commonly used psoriasis mouse model\u003csup\u003e23\u003c/sup\u003e. Notably, the rapid expansion of dWAT has also been observed under other inflammatory conditions, particularly in contexts where neutrophil activity predominates, such as bacterial infection\u003csup\u003e18,19\u003c/sup\u003e and wounding\u003csup\u003e15,39\u003c/sup\u003e. The capacity of dWAT to perceive inflammatory signals hinges upon the expression of diverse cytokine receptors. Here, we demonstrate that pAds express high levels of IL1R, thereby enabling them to sense IL1β released by infiltrating neutrophils. This aligns with existing literature that positions dermal fibroblasts as pivotal sensors of IL1, particularly when released by damaged keratinocytes\u003csup\u003e40\u003c/sup\u003e. Furthermore, the Anxa3\u003csup\u003e+\u003c/sup\u003eLy6A\u003csup\u003e+\u003c/sup\u003e adipocyte progenitors identified in our study has been recognized as T(H)2-interacting fascial fibroblasts (TIFF) \u003csup\u003e41\u003c/sup\u003e. These hypodermal TIFFs expand in response to TH2 cytokines, thereby promoting Th2 T cell polarization and contributing to the formation of hypodermal fibrous bands\u003csup\u003e41\u003c/sup\u003e. Collectively, these studies suggest that lipogenic fibroblasts within dWAT, which is the skin\u0026rsquo;s deepest defensive layer, act as crucial sensors and immunomodulators, participating in the intricate cascade of inflammation orchestrated by IL1 and/or TH2 cytokines.\u003c/p\u003e \u003cp\u003eThe presence of neutrophils in skin lesions is a histopathological hallmark of psoriasis\u003csup\u003e5\u003c/sup\u003e. While keratinocytes release the chemokines CXCL1 and IL-8 to recruit neutrophils to the epidermis\u003csup\u003e42,43\u003c/sup\u003e, the dermal mechanism for neutrophil recruitment is less understood. In situ hybridization and immunostaining analysis of psoriatic skin sections revealed that while IL8 was primarily detected in the upper epidermis by keratinocytes, CXCL1 expression was also strongly expressed in the dermis\u003csup\u003e44\u003c/sup\u003e,, suggesting a dermal source for this chemokine. This study demonstrate that the inflammatory PDGFRA\u003csup\u003e+\u003c/sup\u003e pAd are a prominent dermal source for CXCL1, which in turn acts on neutrophils to enhance IL1β and CXCL2 expression and to induce neutrophil chemotaxis. In addition, we identified SAA3, a major acute-phase protein produced during inflammation\u003csup\u003e45\u003c/sup\u003e, as a marker for pAds activated by IL1β. In mice, \u003cem\u003eSaa3\u003c/em\u003e encodes a functional SAA protein and is the major SAA isoform in inflammatory tissues\u003csup\u003e46,47\u003c/sup\u003e, and IL1 is found the major cytokine responsible for SAA3 induction through a NFKB-and C/EBP dependent mechanism\u003csup\u003e48\u0026ndash;50\u003c/sup\u003e, aligning with our findings. SAA proteins possess cytokine-like properties, participating in cytokine synthesis, chemotaxis of myeloid cells, and activation of the inflammasome cascade\u003csup\u003e45,51\u003c/sup\u003e. SAA3 is also highly expressed in adipose tissue during hyperglycemia and obesity, promoting adipose tissue inflammation\u003csup\u003e52,53\u003c/sup\u003e. Our results showed that the knockdown of \u003cem\u003eSaa3\u003c/em\u003e in activated pAds reduced the ability of pAd to induce the expression of the NO synthase (\u003cem\u003eNos2\u003c/em\u003e), but not \u003cem\u003eIL1b\u003c/em\u003e and \u003cem\u003eCxcl2\u003c/em\u003e in neutrophils, suggesting that pAds contribute to oxidative stress in neutrophils through SAA3 production.\u003c/p\u003e \u003cp\u003eThe topical application of imiquimod is a widely used acute model for psoriasis-like inflammation, but this model is limited by the development of self-tolerance after one-week of application as shown in this study and other studies\u003csup\u003e54,55\u003c/sup\u003e. Nevertheless, the precise mechanisms behind this acquired tolerance are not understood. In this study, we discovered that prolonged exposure of preadipocytes with IL1β eventually leads to the upregulation of PPARγ, which drives the differentiation of proinflammatory CXCL1\u003csup\u003e+\u003c/sup\u003eSAA3\u003csup\u003e+\u003c/sup\u003e preadipocytes into anti-inflammatory early adipocytes, thereby contributing to the resolution of psoriatic skin inflammation. These results are in line with our previous report, which showed that activating IL1R signaling in preadipocytes induces NFκB-dependent phosphorylation of CREB1, subsequently triggering the expression of CEBP/β and PPARγ to initiate adipogenesis during skin development and wound healing\u003csup\u003e15\u003c/sup\u003e. Stimulated PPARγ exerts its anti-inflammatory effect by binding to NFκB at NFκB target genes\u003csup\u003e56\u003c/sup\u003e such as \u003cem\u003eCxcl1\u003c/em\u003e and \u003cem\u003eSaa3\u003c/em\u003e. Additionally, we identified PRG4, an extracellular matrix protein known for its role in reducing joint shear stress\u003csup\u003e57\u0026ndash;59\u003c/sup\u003e, as a marker for differentiating pAds. PRG4 has an anti-inflammatory function; it can bind to toll-like receptors 2 and 4, potentially inhibiting their downstream signaling pathways and reducing the recruitment of proinflammatory macrophages\u003csup\u003e57\u0026ndash;59\u003c/sup\u003e. Further research is necessary to fully understand the role of PRG4 in modulating the anti-inflammatory functions of differentiating preadipocytes in the context of psoriasis pathogenesis.\u003c/p\u003e \u003cp\u003eOur data suggest that the dysregulation of lipogenic fibroblasts may play a role in the chronic inflammation associated with human psoriasis. In human skin, the dermal microvascular structures situated in the dermal-epidermal junction region are particularly enriched with CD34\u003csup\u003e+\u003c/sup\u003e mesenchymal stem cells (MSC)\u003csup\u003e60\u003c/sup\u003e. These MSCs resembles murine \u003cem\u003eCd34\u003c/em\u003e\u003csup\u003e+\u003c/sup\u003e APs residing in the perivascular niche, which is required to maintain their pluripotency\u003csup\u003e61\u0026ndash;63\u003c/sup\u003e. By analyzing human psoriatic scRNAseq data, we identified a subset of dFBs that are enriched with pAd and IL1-pathway signatures, resembling the inflammatory pAd cluster observed in the IMQ-treated murine skin. A recent study utilizing single-cell and spatial RNA sequencing has identified a subset of SFRP2\u003csup\u003e+\u003c/sup\u003e fibroblasts in psoriasis contributing to amplification of the immune network by adopting a proinflammatory phenotype, with IL1β identified as a primary driver of fibroblast inflammation\u003csup\u003e64\u003c/sup\u003e. SFRP2, recognized as an adipokine secreted from undifferentiated AP/pAd\u003csup\u003e65\u0026ndash;67\u003c/sup\u003e, was found to be selectively expressed in APs among all dFB subsets (Fig. S2D). Notably, we found that human pAd cluster also co-enriched with pathways related to inhibitors of adipocyte differentiation, including WNT and TGFβ\u003csup\u003e15,18\u003c/sup\u003e, suggesting that the adipogenic differentiation of these cells into an anti-inflammatory state may be impeded in psoriasis. Consistent with this, we observed an inverse correlation between the expression levels of adipogenesis markers, including \u003cem\u003ePRG4\u003c/em\u003e, \u003cem\u003eFABP4\u003c/em\u003e, and/or \u003cem\u003ePPARG\u003c/em\u003e, and markers of neutrophilic inflammation in human psoriasis. This correlation could potentially serve as a biomarker to distinguish between plaque psoriasis (PV) and generalized pustular psoriasis (GPP), the latter of which is characterized by excessive presence of neutrophils\u003csup\u003e9,38\u003c/sup\u003e. Our findings suggest that the suppression of the adipogenic potential in proinflammatory fibroblasts may be an intrinsic mechanism contributing to the relentless neutrophilic inflammation observed in GPP.\u003c/p\u003e \u003cp\u003eWe have demonstrated that early adipocytes, as opposed to mature adipocytes, secrete anti-inflammatory lipids that help to reduce neutrophilic inflammation. However, a limitation of our study is the yet unidentified nature of these specific bioactive lipids. Moreover, we observed an initial lipolysis event that precedes the re-expansion of dWAT and the subsequent differentiation of adipocytes during IMQ treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), but the functional significance of this initial lipolysis in the context of the adipocyte differentiation process remain to be elucidated. Lipolysis is recognized to be interconnected with de novo lipogenesis, as the free fatty acids (FA) released from the hydrolysis of triglycerides have the potential to be recycled into new lipids and these FA also act as ligands to activate PPARγ\u003csup\u003e68\u003c/sup\u003e. Future lipidomic study is required to determine the identity of the bioactive lipids secreted by early adipocytes, and to explore whether the initial lipolysis event facilitates subsequent de novo lipogenesis by supplying fatty acids.\u003c/p\u003e \u003cp\u003eIn summary, our study has discovered a previously unrecognized mechanism by which the skin develops a tolerance to neutrophilic inflammation. The exploration of strategies aimed at transitioning proinflammatory adipogenic fibroblasts into anti-inflammatory adipocytes, could represent a promising avenue for developing innovative treatments for neutrophil-driven skin disorders, such as psoriasis and ulcers.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eData and Code Availability\u003c/h2\u003e \u003cp\u003eThe accession numbers for the raw data files of the scRNA-seq and snRNA-seq analyses reported in this paper are deposited in the GEO database under accession codes: GSE238086, GSE238085\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eAnimals and animal cares:\u003c/h2\u003e \u003cp\u003eAll animal experiments were approved by the Institutional Animal Care and Use Committee of Xiamen University. C57BL/6 mice, 7\u0026ndash;9 weeks old, were purchased from GemPharmatech (Nanjing, China). \u003cem\u003ePdgfra-\u003c/em\u003eC\u003cem\u003ere\u003c/em\u003eERT2 mice (Stock No: 032770) and ROSA-\u003cem\u003emT/mG\u003c/em\u003e mice (Stock No: 07676) were originally purchased from Jackson laboratory. \u003cem\u003ePparg\u003c/em\u003e\u003csup\u003e\u003cem\u003eflox/flox\u003c/em\u003e\u003c/sup\u003e mice were generously provided by professor Yuling Shi (Tongji University, Shanghai, China). Fibroblast specific \u003cem\u003ePparg\u003c/em\u003e knockout mice were generated by breeding \u003cem\u003ePparg\u003c/em\u003e\u003csup\u003e\u003cem\u003eflox/flox\u003c/em\u003e\u003c/sup\u003e with \u003cem\u003ePdgfra-\u003c/em\u003eC\u003cem\u003ere\u003c/em\u003eERT2. \u003cem\u003eIl1r1\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u0026minus;/\u0026minus;\u003c/em\u003e\u003c/sup\u003e mice were generously provided by professor Jiahuai Han (Xiamen University, Xiamen, Fujian, China). All mice were bred and maintained in standard pathogen free environment of the Laboratory Animal Center in Xiamen University.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eHuman skin sample collection and analysis:\u003c/h2\u003e \u003cp\u003eFresh adult human full thickness skin biopsies, from age and sex matched healthy, psoriasis donors were collected by the department of dermatology at Shanghai Skin Disease hospital. Patients with psoriasis vulgaris or Generalized pustular psoriasis (GPP) were diagnosed based on their clinical appearance. All sample acquisitions were approved and regulated by Medical Ethics Committee of the Shanghai Skin Disease hospital (reference number No. 2023-04). All donors provided the informed consent before skin biopsies. Upon collection, these samples were directly fixed with PFA and then proceed for paraffin embedding for histological or immunofluorescent analyses.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eIMQ-induced Psoriasis-like mouse model and treatment procedures\u003c/h2\u003e \u003cp\u003e7\u0026thinsp;~\u0026thinsp;9 weeks old C57BL/6 mice (sex-matched) were anesthetized using isoflurane, and dorsal skin was shaved, depilated, then topically applied with a dose of 45mg IMQ cream (5%, MedShine, 120503) over a 2 cm\u003csup\u003e2\u003c/sup\u003e surface area for 6 consecutive days. The severity of skin inflammation was evaluated daily using the Psoriasis Area and Severity Index (PASI) as described previously \u003csup\u003e69,70\u003c/sup\u003e. For lineage tracing of \u003cem\u003ePdgfra\u003c/em\u003e\u003csup\u003e\u003cem\u003e+\u003c/em\u003e\u003c/sup\u003e dFBs, \u003cem\u003ePdgfra-Cre\u003c/em\u003eERT2; \u003cem\u003emTmG\u003c/em\u003e mice were daily received an intraperitoneal injection of tamoxifen (TAM) (Sigma, T5648) dissolved in corn oil (Selleck, s6701) at 50mg/kg body weight for 4 consequent days during IMQ treatment. To deplete neutrophils, mice were intraperitoneally administrated with 50 \u0026micro;g of anti-LY6G (Biolegend, 127649) or IgG2a isotype control antibody (Biolegend, 400565) from one day after IMQ treatment to the end of the experiment. For CXCL1 blockade, 20 \u0026micro;g of anti-CXCL1 antibody (R\u0026amp; D Systems, MAB453) or rat IgG2A isotype control antibody (R\u0026amp;D Systems, MAB006) were injected intravenously at a 2-days interval starting from one day before IMQ treatment to the end of the experiment. To antagonize PPARγ signaling, mice were injected intraperitoneally with 30mg/kg of BADGE (Sigma, D3415) two days after IMQ treatment to the end of the experiment, and 10% DMSO in PBS was used as control. For in vivo application of eAd-CM, 200 \u0026micro;l of blank medium or eAd-CM were injected i.p. to mouse back skin during IMQ application. For topical application of eAd_lipids, 1 mg highly purified Sponge Haliclona sp. spicules (SHS)\u003csup\u003e35,36\u003c/sup\u003e was resuspended in 100 \u0026micro;l of lipid fractions isolated from blank medium or eAd-CM, and the mixture was then dripped onto IMQ-treated area of skin, followed by massaging dorsal skin for 2 min.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eSingle-cell or Single-nuclei RNA library preparation and sequencing:\u003c/h2\u003e \u003cp\u003eBriefly, dorsal skin biopsies were collected from healthy control and IMQ-treated C57BL/6 mice, and skin biopsies were subjected to mincing and enzymatic digestion by collagenase D and DNase1 to isolate single cell as described previously \u003csup\u003e15,16,71\u003c/sup\u003e. Dead cells were removed using DeadCell Removal kit (Miltenyi Biotic,130-090-101) according to manufacturer\u0026rsquo;s instruction. To isolate single-nuclei, fresh skin tissues were preserved by snap freezing in liquid nitrogen, transferred to a dounce homogenizer, grinded into a homogenate in lysis buffer. Nuclei were extracted by repeated washes with nuclear resuspension buffer and sucrose cushion buffer, then isolated nuclei were further purified by DAPI staining and sorting. Live single cells or single nuclei were loaded on a 10x Genomics GemCode Single-cell instrument that generates single-cell Gel Bead-In-EMlusion (GEMs). Single-cell or single-nuclei libraries were prepared using Chromium Next GEM Single Cell 3\u0026rsquo; Reagent Kits v3.1. cDNA libraries were sequenced on an Illumina Novaseq6000 platform (Illumina).\u003c/p\u003e \u003cp\u003eDetailed methods for data processing, including quality control, unsupervised clustering, gene expression analysis, and bioinformatic analyses including Monocle pseudotime analysis, CytoTRACE analysis, RNA velocity analysis, muti-volcano differential expression analysis, gene-set enrichment score analysis, Pearson Correlation analysis, cell-chat signaling network analysis can be found in the supplemental method section. Single cell RNA libraries construction, sequencing and bioinformatic analysis was assisted by GENE DENOVO Inc (Guangzhou, China).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003ePrimary mouse dermal fibroblast isolation and in vitro adipocyte differentiation:\u003c/h2\u003e \u003cp\u003ePrimary mouse dermal fibroblasts (dFBs) were isolated from neonatal or adult mouse skin by enzymatic digestion with dispase, Collagenase D, and DNAse1 as shown previously\u003csup\u003e16,71\u003c/sup\u003e. Isolated dFBs were cultured in growth medium (DMEM supplemented with 10% FBS and antibiotics/antimycotics) in a humidified incubator at 5% CO2 and 37\u0026deg;C under sterile conditions, and only passage 1 cells were used for experiment. To collect CM from IL1β-primed dFBs, cells were treated with IL1β for 2h and medium was replaced with fresh medium without IL1β for additional 48 hours before collection. To induce adipocyte differentiation, two days post-confluent dFB were switched to adipocyte differentiation medium containing 2 \u0026micro;M Dexamethasone, 250 \u0026micro;M IBMX, 200 \u0026micro;M Indomethacin and 10 \u0026micro;g/mL recombinant human insulin. Fresh differentiation medium was changed at day 3 then medium was switched to maintenance medium (growth medium supplemented with 10 \u0026micro;g/mL recombinant human insulin) to promote maturation and hypertrophy of differentiated adipocytes. Adipocytes were stained with Oil-red-O (ORO) to detect lipid-droplets as described previously\u003csup\u003e72\u003c/sup\u003e. The percentages of ORO-positive areas were quantified using ImageJ software.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eAdipocyte conditioned medium collection and lipid extraction\u003c/h2\u003e \u003cp\u003eAdipocytes at indicated differentiation days were maintained in serum free medium containing 10 \u0026micro;g/mL recombinant human insulin for 3 days before conditioned medium (CM) was collected and centrifuged to remove cell debris. To heat inactivate protein, Ad-CM was heated at 95℃ for 15 mins on heat block. Proteins and lipids extraction was performed as described by Matyash (Matyash et al., 2008). Briefly, Methyl tert-Butyl Ether (MTBE)/Methanol was added to CM (10:3:2.5, v/v/v) and the mixture were vortexed for 1 min before centrifugation for 15min at 3,000 g. The lipid-containing upper layer and the protein precipitation were collected separately, and then dried under a gentle stream of nitrogen gas at 37˚C followed by resuspension in DMEM/F12 to an identical final volume for cell treatment or in vivo application.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003ePrimary neutrophil and macrophage isolation and in vitro culture:\u003c/h2\u003e \u003cp\u003ePrimary bone marrow-derived neutrophils and peritoneal macrophages were isolated and cultured as described in the supplemental method section. For co-culture assays, neutrophils or macrophages were pretreated with CM collected from dFBs or adipocytes (50% volume), then stimulated without or with FSL (50 ng/mL) for 6 hours or LPS (500 ng/mL) for 12 hours. To block CXCL1 activity, adipocyte-conditioned medium was pre-incubated with anti-CXCL1 neutralizing antibody (R\u0026amp;D Systems, MAB453) or rat IgG2A isotype control antibody (R\u0026amp;D Systems, MAB006) for one hour at 37\u0026deg;C before the CM was applied to neutrophils. For neutrophil transmigration assay, neutrophils were isolated from ROSA-mT/mG mice and were placed to the top of the Transwell\u0026reg; inserts, and dFB-CM were added to the bottom of each well. 2 hours after the co-culture, neutrophils transmigrated to the lower chamber were fixed and stained with FITC-Ly6G antibody (eBioscience, 11593182). The percentage of Tomato\u0026thinsp;+\u0026thinsp;Ly6G\u0026thinsp;+\u0026thinsp;neutrophils were imaged and counted by confocal fluorescence microscopy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eQuantification and statistical analysis\u003c/h2\u003e \u003cp\u003eExperiments were repeated at least 3 times with similar results and the data were statistically analyzed using GraphPad Prism (version 9.0.0). Quantification analyses of Immunofluorescence sections showing the fluorescence integrated intensity of indicated fluorophores were performed by ImageJ (version 1.53). Quantified intensity profiles showing signals from indicated fluorescent channels across skin sections (from top to bottom) is adapted from publications \u003csup\u003e73,74\u003c/sup\u003e. Statistical significance was determined using Student\u0026rsquo;s unpaired two-tailed t-test to compare two conditions or one-way ANOVA for multiple comparisons. The probability values of \u0026lt;\u0026thinsp;0.05 were considered statistically significant (*P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **P\u0026thinsp;\u0026lt;\u0026thinsp;0.01, ***P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, ****P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCONFLICT OF INTERESTS\u003c/h2\u003e \u003cp\u003eAll authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAUTHOR CONTRIBUTIONS\u003c/h2\u003e \u003cp\u003eConceptualization, T.X, W.Z, R.W., M.C., and L.Z.; methodology, T.X, W.Z, R.W., X.Z., R.X., C.Z., W.L., and L.Z.; investigation, T.X, W.Z, R.W., X.Z., R.X., X.H., S.W., Yanhang.L., J.L., Youxi.L., Yiman.L., Z.G., and W.L.; resources, M.C., J.L., and Y.S.; data curation, T.X, W.Z, R.W., and L.Z.; writing-original draft, T.X, W.Z, R.W., and L.Z.; writing-review and editing, M.C., J.L., Y.S., and L.Z.; supervision, L.Z.\u003c/p\u003e\u003ch2\u003eACKNOWLEDGMENTS\u003c/h2\u003e \u003cp\u003eL-J. Z. is supported by National Key R\u0026amp;D Program of China (2023YFC2508102) and NSFC (82373879 and 81971551). We thank Dr. Jiahuai Han from Xiamen University for providing the \u003cem\u003eIL1r1\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u0026minus;/\u0026minus;\u003c/em\u003e\u003c/sup\u003e mice and Dr. Yuling Shi from Fudan University for providing the \u003cem\u003ePparg-floxed\u003c/em\u003e mice. We thank the flow-cytometry and confocal microscopic core facility at Xiamen university for flow-cytometry, sorting and imaging studies.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePeiseler, M. \u0026amp; Kubes, P. More friend than foe: the emerging role of neutrophils in tissue repair. \u003cem\u003eJ Clin Invest\u003c/em\u003e \u003cstrong\u003e129\u003c/strong\u003e, 2629-2639 (2019). https://doi.org:10.1172/JCI124616\u003c/li\u003e\n\u003cli\u003eQu, J., Jin, J., Zhang, M. \u0026amp; Ng, L. G. 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N.\u003cem\u003e et al.\u003c/em\u003e Fluorescence microscopy colocalization of lipid-nucleic acid nanoparticles with wildtype and mutant Rab5-GFP: A platform for investigating early endosomal events. \u003cem\u003eBiochim Biophys Acta\u003c/em\u003e\u003cstrong\u003e1848\u003c/strong\u003e, 1308-1318 (2015). https://doi.org:10.1016/j.bbamem.2015.03.001\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cellular-and-molecular-immunology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"cmi","sideBox":"Learn more about [Cellular \u0026 Molecular Immunology](http://www.nature.com/cmi/)","snPcode":"41423","submissionUrl":"https://mts-cmi.nature.com/cgi-bin/main.plex","title":"Cellular \u0026 Molecular Immunology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Skin inflammation, Psoriasis, Neutrophils, Inflammation resolution, Fibroblasts, Adipogenesis, Adipocytes, Preadipocytes, IL1, PPARγ ","lastPublishedDoi":"10.21203/rs.3.rs-4346630/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4346630/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe skin\u0026rsquo;s immune response to danger signals involves rapid recruitment of neutrophils, but their excessive accumulation leads to inflammatory skin diseases, such as psoriasis, and how skin resident cells tolerate neutrophilic inflammation is poorly understood. Dermal white adipose tissue (dWAT) is an emerging component of the skin's immune barrier, but its role in controlling skin inflammation remains under-studied. Here, using an imiquimod-induced psoriasis mouse model, we observed a dynamic coupling between dermal adipogenesis, neutrophil infiltration and regression. During the early inflammatory phase, dWAT repopulates with PDGFRA\u003csup\u003e+\u003c/sup\u003e preadipocytes that secrete CXCL1 and SAA3, attracting and activating CXCR2\u003csup\u003e+\u003c/sup\u003e neutrophils. These neutrophils further activate preadipocytes through IL1β-IL1R signaling, establishing a self-sustaining inflammatory loop. Prolonged activation of pAds triggers PPARγ-dependent adipogenesis, leading to the formation of early adipocytes that secrete lipids exerting potent anti-inflammatory activity against myeloid cells, thereby aiding in inflammation resolution. Inhibition of adipogenesis, via targeted inhibition of PPARγ, through either pharmacological or genetic approaches, disrupts the formation of early adipocytes and prevents neutrophil regression and inflammation resolution. Analysis of human psoriatic cells identified a dFB subpopulation enriched with preadipocyte, IL1-pathway, and inflammatory gene signatures. Furthermore, transcriptomic analyses revealed a negative correlation between neutrophil-related inflammatory response with dermal adipogenesis response in generalized pustular psoriasis. Together, this study highlights the distinct roles of adipogenic fibroblasts and early adipocytes in initiating and resolving skin inflammation and suggests that promoting the differentiation of proinflammatory fibroblasts into anti-inflammatory early adipocytes could open avenues for the treatment of neutrophil-related inflammatory skin diseases, such as psoriasis and ulcers.\u003c/p\u003e","manuscriptTitle":"Dermal adipogenesis protects against neutrophilic skin inflammation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-17 18:26:38","doi":"10.21203/rs.3.rs-4346630/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-07-08T07:07:18+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-07-06T19:32:36+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-20T13:24:26+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-14T15:49:02+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-13T18:31:43+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-03T10:17:15+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-05-29T13:24:35+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-05-08T20:19:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-07T03:47:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-07T01:23:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cellular \u0026 Molecular Immunology","date":"2024-05-06T09:51:03+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2024-04-30T10:02:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cellular-and-molecular-immunology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"cmi","sideBox":"Learn more about [Cellular \u0026 Molecular Immunology](http://www.nature.com/cmi/)","snPcode":"41423","submissionUrl":"https://mts-cmi.nature.com/cgi-bin/main.plex","title":"Cellular \u0026 Molecular Immunology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ee296ec8-13bc-4456-b9c9-1682ff827e60","owner":[],"postedDate":"May 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":31692613,"name":"Biological sciences/Immunology/Inflammation"},{"id":31692614,"name":"Biological sciences/Cell biology/Cell signalling/Stress signalling"},{"id":31692615,"name":"Biological sciences/Immunology/Inflammation"},{"id":31692616,"name":"Biological sciences/Cell biology/Cell signalling/Stress signalling"},{"id":31692623,"name":"Biological sciences/Immunology/Inflammation"},{"id":31692624,"name":"Biological sciences/Cell biology/Cell signalling/Stress signalling"}],"tags":[],"updatedAt":"2025-06-24T07:06:51+00:00","versionOfRecord":{"articleIdentity":"rs-4346630","link":"https://doi.org/10.1038/s41423-025-01296-5","journal":{"identity":"cellular-and-molecular-immunology","isVorOnly":false,"title":"Cellular \u0026 Molecular Immunology"},"publishedOn":"2025-06-23 04:00:00","publishedOnDateReadable":"June 23rd, 2025"},"versionCreatedAt":"2024-05-17 18:26:38","video":"","vorDoi":"10.1038/s41423-025-01296-5","vorDoiUrl":"https://doi.org/10.1038/s41423-025-01296-5","workflowStages":[]},"version":"v1","identity":"rs-4346630","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4346630","identity":"rs-4346630","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}