The bidirectional neuroimmune dialogue in inter-organs

The bidirectional neuroimmune dialogue in inter-organs | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 7 October 2025 V1 Latest version Share on The bidirectional neuroimmune dialogue in inter-organs Authors : Wenqian Huang , Xiangyang Wang , and Yingjiao Cao 0009-0004-9367-9792 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175983149.90056770/v1 180 views 153 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract The long-established perception envisioning the brain as an immune-privileged organ has undergone a paradigm shift in recent decades. Emerging research reveals that the nervous and immune systems engage in bidirectional crosstalk through anatomically specialized niches and closely entwined molecular axes to maintain tissue homeostasis, modulate immune responses and ensure properly neural function. Unfortunately, the bidirectional neuroimmune dialogue can also malfunction under some circumstances, leading to a spectrum of diseases including neuroinflammatory disorders, metabolic disorders and cancer. Here we summarize recent advances revealing the neuroimmune interaction under physiologic and pathologic processes, focusing on neuronal regulation of immune responses in barrier tissues and the reciprocal influence of immune cells on neural development and brain function. The bidirectional neuroimmune dialogue in inter-organs Wenqian Huang 1 , Xiangyang Wang 2,3 *, Yingjiao Cao 1,3 * 1 Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. 2 Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China. 3 Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital Ganzhou Hospital，Guangdong Academy of Medical Sciences, Guangzhou, China. *Correspondence: [email protected] (YC) Abstract The long-established perception envisioning the brain as an immune-privileged organ has undergone a paradigm shift in recent decades. Emerging research reveals that the nervous and immune systems engage in bidirectional crosstalk through anatomically specialized niches and closely entwined molecular axes to maintain tissue homeostasis, modulate immune responses and ensure properly neural function. Unfortunately, the bidirectional neuroimmune dialogue can also malfunction under some circumstances, leading to a spectrum of diseases including neuroinflammatory disorders, metabolic disorders and cancer. Here we summarize recent advances revealing the neuroimmune interaction under physiologic and pathologic processes, focusing on neuronal regulation of immune responses in barrier tissues and the reciprocal influence of immune cells on neural development and brain function. Immune and nervous system are intricately intertwined Brain has long been considered as an immune-privileged organ since the purported absence of lymphatic vessel and the limited rejection of xenobiotic tissue by the brain (1). However, experimental and clinical evidence has posed a challenge to the long-established paradigm (2,3). Immune cells reside in the specialized niches of central nervous system (CNS) and contribute to the circuit refinement and neuronal function (4,5). Meanwhile, peripheral nervous system (PNS) also innervates spleen, lymph node and even tumors to modulate immune responses (6–8). Beyond anatomical connection, those two systems also have considerable overlaps and well-organized crosstalk, cooperating to support development and maintain homeostasis of an organism. Neurotransmitters, neuropeptides and neural hormones participate in immune regulation, while many signaling molecules and pathways characterized in the immune system are increasingly recognized as critical for normal brain function (9,10). Collectively, these findings reveal that the immune and nervous system are not only anatomically interlinked but also functionally integrated, highlighting the urgency to unravel the molecular underpinnings of such sophisticated neuroimmune dialogue. Recent technological innovations such as chemogenetics, optogenetics and spatially resolved single-cell technologies are enabling a deeper interrogation of molecular and cellular basis of the neuroimmune interactions. Owing to the ever-increasing advancement and the great abundance of paper on the subject, this review is not exhaustive but instead highlights pivotal discoveries that redefine our understanding of neuroimmune crosstalk. Here we detail the recent advances in neural regulation of immune cells in the context of homeostasis, host-defense, hypersensitivity and cancer, emphasizing context-dependent mechanisms of neuroimmune dialogue in inter-organs. We also examine how innate and adaptive immune cells influence neural development, plasticity and function, highlighting conserved pathways and their translational implications. Elucidating the spatiotemporal dynamics of these interactions represents a vibrant frontier and will accelerate the development of effective therapies for diseases such as metabolic disorders, cancer and neurological disorders . Elaborate regulation of immune responses by neurons The nervous system is comprised of the CNS (brain and spinal cord) and the PNS (sensory and autonomic components), the latter can be subdivided into somatic and visceral arms (Fig. 1A). The cell bodies of the sensory neurons reside within trigeminal ganglia (TG) in the cranium and dorsal root ganglia (DRG) near the spinal cord, conveying information about pain, temperature and touch to CNS (Fig. 1B) (11). The autonomic nervous system can be further classified into parasympathetic, sympathetic and enteric nervous system (ENS) (Fig. 1C). The parasympathetic neurons are hardwired into the visceral organ through the vagal nerve, modulating heart, lung and intestine via the transmitter acetylcholine (Ach) (12). Sympathetic neurons mediate ”fight-or-flight” responses through catecholamines such as epinephrine, norepinephrine (NE) and dopamine (13). ENS is located within the myenteric and submucosal plexus of the intestine, senses local stimuli and regulates motility and secretion (14). Upon activation, sensory neurons conduct signals orthodromically to the CNS, generating sensations such as pain or itch. Concurrently, the conducted action potentials transmit antidromically toward the PNS and cause the rapid release of neurotransmitters such as Ach, catecholamine and glutamine, and neuropeptides such as neuromedin U (NMU), calcitonin gene relating peptide (CGRP) and vasoactive intestinal polypeptide (VIP), to modulate immune responses via the cascades of subsequent signal pathways (15). As the neuronal sensing and response occur on a timescale of milliseconds and span the entire body, this neuronal control of immune system enables an accelerated reaction rate and extended physiological reach, highlighting the evolutionary significance of such a regulation system. In this part, we highlight key discoveries in neural-immune regulation across homeostasis, host-defense, hypersensitivity and cancer. Future exploration will continue to yield important insights into how the nervous system shape immunity in a context-dependent way. Homeostasis PNS innervates peripheral organs and tissues to modulate immune responses, supporting homeostasis, tissue repair and metabolic regulation. The intestine, as a major immune site, is densely innervated by neurons and serves as a hub for neuroimmune communication. For instance, the circadian neuropeptide VIP is released by enteric neurons upon food intake to regulate group 3 innate lymphoid cell (ILC3) response while promoting lipid uptake (Fig. 2A) (16,17). This feeding-regulated circuit illustrates how organisms coordinate nutrient assimilation with barrier immunity. Notably, the VIP could also potentiates the IL-5 secretion by group 2 innate lymphoid cell (ILC2), linking neural circadian rhythms to eosinophil homeostasis (Fig. 2A) (18,19). As suprachiasmatic nuclei in the hypothalamus integrates external light cues, the neural circuits may regulate the ILC response to avoid excess activation during homeostasis while assuring adequate immune response against ingested pathogens, although more specific mechanisms remains to be elucidated (20). Beyond ILCs, a reciprocal loop exists between muscularis macrophages (MMs) and enteric neurons. MMs produce BMP2 to trigger neuronal release of colony stimulatory factor 1 (CSF1) essential for MM development requisite for MMs development (Fig. 2A) (21). Recently, MMs were shown to refine ENS synapses, which in turn sustain neuro-supportive phenotype of MMs through transforming growth factor-β (TGF-β) signaling (22). This self-sustaining neuroimmune unit emerges as a bona fide therapeutic target for gut motility disorders. Gut-innervated sensory neurons further amplify this neuroimmune dialog. Nav1.8 + nerves could elicit mucus secretion by goblet cells via CGRP-Ramp1 axis, orchestrating intestine microbiota homeostasis and mucosal barrier protection (Fig. 2A) (23). Similarly, TRPV1⁺ neurons release SP, promoting goblet cell proliferation in a microbiota-dependent manner, indicating a sophisticated functional link between nociceptors, immune cells and intestine microbiota (Fig. 2A) (24). Gut-innervated sympathetic neurons secret NE to promote ILC2 migration to pancreas, ILC2-derived IL-5/IL-13 subsequently stimulate pancreatic α-cell glucagon secretion to modulate glucose homeostasis (Fig. 2B) (25). In adipose tissue, sympathetic neuron-released NE trigger the release of glial cell line-derived neurotrophic factor (GDNF) by mesenchymal cell, which boosts ILC2s-mediated energy expenditure, suggesting therapeutic potential of targeting neuroimmune axis in treating obesity and metabolic disorders (Fig. 2B) (26). In the skin, Nav1.8 + nociceptors suppress phagocyte infiltration via CGRP-RAMP1 signaling while polarizing macrophages towards M2 phenotype (Fig. 2C) (27). Notably, TRPA1 activation in nociceptors induces IL-23 production from dermal dendritic cells (dDCs), driving γδ T cell-mediated IL-17/IL-22 production to accelerate tissue regeneration (Fig. 2C) (28). Similarly, GINIP + mechanoreceptors secrete TAFA4 to promote IL-10 + macrophage survival critical for tissue repair. In parallel, Langerhans cells also regulate MrgprD⁺ neurons to suppress mast cell MrgprB2 expression, curbing mast cell hyperreactivity and maintaining cutaneous immune homeostasis (Fig. 2C) (29). Collectively, these findings demonstrate how neuroimmune interactions dynamically coordinate metabolic and reparative processes across tissues and harnessing neuronal responses via methods like chemogenetics and optogenetics could offer a promising strategy for treating inflammatory and metabolic diseases. Host-defense The nervous system detects microbial pathogens at barrier sites and orchestrates anti-microbial responses via neuroimmune crosstalk, exerting systemic effects on host defense. During viral infection, prostaglandin E₂ (PGE₂) activates splenic nociceptors to release CGRP, which enhances B cell germinal center response via RAMP1 and strengthens anti-influenza immunity (6). GCRP also promotes Th1 cells differentiation via RAMP3, amplifying anti-viral CD8 + T cell and Th1 cell response (30). In contrast, glossopharyngeal GABRA1 + neurons activated by PGE2 during influenza infection exacerbate sickness behaviors (Fig. 3B) (31). The discrepancy indicates the context-dependent duality of neuroimmune interplay, which may be attributed to neuron subtypes and signaling hubs engaged. The interaction between bacteria and host immunity could bring about a wide spectrum of consequences spanning from mutualistic symbiosis to pathogenic aggression. Notably, bacteria-derived signals also hijack neural circuits to modulate social behaviors and sculpt the host immune landscape via neuroimmune crosstalk (32,33). In the skin, Staphylococcus aureus ( S. aureus ) serine V8 protease activates the pruriceptors via protease-activated receptor 1 (PAR1) to drive itch, while NFP and α-HL trigger pain via formyl peptide receptors (FPRs) and ADAM10, respectively (34,35). Once activated, nociceptors concurrently release CGRP to suppress the neutrophils infiltration and TNF-α production by macrophages (Fig. 3A) (35). Similarly, Streptococcus pyogenes ( S. pyogenes ) secret streptolyisn S to cause pain and the release of CGRP, impairing neutrophils recruitment and phagocytosis (Fig. 3A) (36). Conversely, in fungal infection, TRPV1 + neuron-derived CGRP enhances defense against cutaneous Candida albicans ( C. albicans ) by driving IL-23 production from CD301 + dDCs, priming IL-17 responses of γδ T cell. (Fig. 3A) (37). Activation of TRPV1 + neurons via optogenetics is sufficient to confer anticipatory protection against C. albicans via a nerve reflex arc (38). This context-specific duality of CGRP signaling illustrates how neuroimmune mechanisms are finely tuned to local microenvironmental cues. The lung and respiratory tract-innervated neurons are closely related with coughing, bronchoconstriction and host-defense against pathogens. For instance, mycobacterium tuberculosis ( Mtb ) produces sulfolipid 1 (SL-1) which activates TRPV1 + neurons to trigger cough, facilitating pathogen transmission (Fig. 3B) (39). During lethal S. aureus pneumonia, TRPV1 + nociceptors secret CGRP to suppress the neutrophil and γδT cell responses, dampening host immunity (Fig. 3B) (40). In parallel, cytosolic CGRP in macrophages could dismantle the NLRP3-NEK7 complex, thereby disrupting the activation of NLRP3 inflammation and dampening the host immunity against Klebsiella pneumoniae (K. pneumoniae) infection (Fig. 3B) (41). Together, those researches highlight the active participation of neuron in host-defense immunity and unravel a novel therapeutic target in treating bacterial pneumonia. The intestine is densely innervated by intrinsic and extrinsic neurons which orchestrate motility, secretion and pathogen defense through neuroimmune interactions. For instance, the ENS-derived IL-18 elicits the production of antimicrobial protein (AMP) from goblet cells (Fig. 3C) (42). Nociceptors also protect against Salmonella by releasing CGRP, which downregulates the microfold cells (M cells) density to limit bacterial entry and maintains the colonization of segmented filamentous bacteria (SFB) to block Salmonella invasion (Fig. 3C) (43). Additionally, commensal microbes activate Nav1.8⁺ neurons to release CGRP, stimulating rapid goblet cell mucus secretion (23). During Salmonella infection, sympathetic neurons release NE to polarize MMs toward M2 phenotype via beta-2 adrenergic receptor (β2AR) (Fig. 3C) (44). CGRP further modulates anti-helminth immunity by enhancing ILC2 proliferation and IL-13 production (45). Notably, a subset of ILC2s express Calca (encoding CGRP), indicating a negative feedback loop during type 2 responses (Fig. 3C) (45). Further complexity arises as enteric neurons sense ILC2-derived IL-13 via IL-13R, reciprocally dampening anti-helminth immunity via CGRP signaling, suggesting a bidirectional neuroimmune checkpoint (46). Similarly, sympathetic neurons also inhibit ILC2 response and helminth clearance through β2AR (Fig. 3C) (47). Conversely, cholinergic neuron-derived neuropeptide NMU potently activates ILC2s and recruits eosinophils to accelerate helminth expulsion (Fig. 3C) (48–50). A recent study has illustrated that NMU can also activate eosinophils to drive the rapid differentiation of goblet cells (Fig. 3C) (51). These findings underscore the highly complexity of neuroimmune interplay during parasite infection and future studies dissecting how neurons decode parasite-derived cues and coordinate different signals to modulate immunity remains an emerging field. Hypersensitivity and cancer The PNS dynamically regulates inflammation through context-specific neuroimmune interactions. For instance, nociceptor neurons boost type 17 immunity as optogenetic activation of TRPV1 + or Nav1.8 + nociceptors induces robust type 17 inflammation (Fig. 4A) (52,53). In contrast, CGRP generally suppresses type 2 responses by acting on ILC2s, mast cells and CD4⁺ T cells. In the lung, CGRP suppresses the type 2 inflammation via CALCRL/RAMP1 expressed on ILC2s, inhibiting IL-13 production and eosinophils recruitment (Fig. 4A) (45,54). Similarly, in the intestine, ChAT⁺ enteric neuron-derived CGRP constrains ILC2 activity and reduces mast cell numbers (55). Paradoxically, pulmonary neuroendocrine cell-derived CGRP exacerbates type 2 asthma, revealing a source-specific duality in CGRP function (Fig. 4A) (56,57). These divergent effects underscore the necessity to delineate how neural microenvironments encode bidirectional immune regulation and evolving whether such contradictions arise from ILC2 heterogeneity or tissue-specific neuroimmune hubs remains a key frontier. Cholinergic neurons amplify type 2 immunity via the NMU/NMUR1 axis, driving ILC2 proliferation and cytokine production in the gut and lung—a mechanism evolutionarily conserved and non-redundant from adaptive immunity (Fig. 4B) (50,58). NMU further activates NMR1 + eosinophils to promote goblet cell differentiation, reinforcing intestinal barrier integrity (Fig. 4B) (59). In parallel, SP is another neuropeptide that also strongly boosts type 2 immunity. In house dust mice (HDM)-induced skin inflammation, TRPV1 + neurons detect cysteine protease and release SP, which induces mast cell degranulation via MRGPRB2 and recruits CD301b⁺ dendritic cells to lymph nodes via MRGPRA1, initiating Th2 responses (Fig. 4C) (60,61). Paradoxically, SP exhibits anti-inflammatory effects in the gut, highlighting tissue-specific neuroimmune duality and offering novel insights into the exploration of neuromodulation-based therapies for inflammatory disorders (Fig. 4C) (62). The circadian synchronizer VIP is another neuropeptide that activates ILC2s and Th2 cells via VIP receptor type 2 (VPAC2), linking type 2 immunity to circadian rhythm and metabolic cues (Fig. 4D) (18,19,63). Noteworthy, IL-5 from ILC2s stimulates Nav1.8 + neurons to secret VIP, creating a positive feedback loop that promotes exacerbates allergic airway inflammation (Fig. 4D) (63). These findings underscore neurons as context-dependent rheostats of immunity, highlighting the potential of targeting specific neuropeptide pathways for immunomodulatory therapy. Neurotransmitters also fine-tune inflammatory responses through context-dependent mechanisms. Adrenergic neurons colocalizing with ILC2s in gut and lung suppress type 2 inflammation via NE-β2AR axis (Fig. 4C) (47,64). Paradoxically, brainstem Dbh + neurons activated by mast cell-derived IL-4 release NE to induce ganglionic parasympathetic neurons to release Ach, which amplifies allergen hypersensitivity (Fig. 4C) (65). These opposing roles of NE underscore the complexity of neuroimmune circuits and highlight the need to delineate how neural and immune components cooperate to balance host defense and pathological inflammation. Dopamine is another member of catecholamines that regulates the inflammation and exhibits age- and receptor-specific duality. In pediatric asthma, sympathetic neurons-derived dopamine promotes the differentiation of Th2 cells and the establishment of Th2 resident memory cells through dopamine receptor 4 (DRD4) (Fig. 6) (66,67). As the sympathetic neurons in the lung undergoes a dopaminergic-to-adrenergic shift during neonatal development, the dopamine-DRD4 signaling might represents the mechanisms underlining the susceptibility of young children to asthma (66). However, our work has demonstrated that dopamine suppresses ILC2-driven allergic lung inflammation via metabolic restriction, which is depending on dopamine receptor 1 (DRD1). Moreover, local administration of dopamine significantly alleviated multiple allergens induced airway inflammations in adults, which highlight that dopamine-DRD1 signals could be harnessed to potentiate immunotherapy for allergic lung inflammations (Fig. 4C) (68). These findings indicate that sympathetic signals may encompass dual mechanisms to activate or repress type 2 inflammation in a context-, age- or disease-dependent manner and more specific mechanisms involved warrants further investigation. Noteworthily, dopamine-DRD1 inhibits the NLRP3 inflammasome activation in macrophages, thereby suppressing multiple systemic inflammation (69). These findings reveal sympathetic pleiotropy in the context of inflammation, positioning adrenergic and dopaminergic pathways as tunable targets for treating relevant diseases. Beyond neuropeptides and neurotransmitters, neuronal hormones such like prostaglandin D2 and neuropeptide Y also participate in the neuroimmune interplay and fine-tune the inflammatory response, working together to synchronize the inflammatory response with physiological function, ultimately supporting the necessary homeostasis of an organism (70,71). Parallel to roles during inflammation, the nervous system is emerging as a crucial regulator of cancer, influencing tumor initiation, progression and metastasis. In turn, tumor cells also hijack and remodel neural circuits to facilitate their growth and dissemination (72). Nerves branches to tumor microenvironment, engaging directly with cancer cells via neuro-cancer synapses or paracrine signaling (72–75). In addition, indirect crosstalk also occurs as circulating and paracrine signals from neurons profoundly affect immune cells trafficking and function. Elucidating the intricate dialogue among nervous system, immune system and cancer represents an emerging frontier with therapeutic implications. In the brain, gliomas synaptically and electrically integrate into neural circuits which cause current amplitude in tumor cells via AMPA receptor or gap junction to promote glioma proliferation (Fig. 5A) (73–76). In parallel, neuronal activity-dependent release of paracrine signals such as brain-derived neurotrophic factor (BDNF), neuroligin-3 and insulin-like growth factor 1 could also accelerate glioma growth (Fig. 5A) (74,77,78). In turn, gliomas remodel synaptic plasticity and neuronal activity through signals like thrombospondin-1, establishing a feedforward loop of tumor progression (Fig. 5A). Beyond CNS, recent studies have come to appreciate the pivotal role of peripheral innervation in the progression of multiple cancers types including head and neck, gastrointestinal, melanoma, breast and pancreatic cancers (72,79–82). PNS-cancer cell crosstalk occurs in a manner which closely mimics the principles under brain tumors, with PNS neurons innervating various cancers and establishing a neuron-cancer-microenvironment interactome. In head and neck cancer, tumor cells reprogram sensory neurons toward an adrenergic phenotype to support tumor progression (79). Gastric tumor cells also secret nerve growth factor (NGF) to induce nociceptive nerve expansion and CGRP release, which drive tumor progression via CGRP-RAMP1 pathways (Fig. 5B) (80). Likewise, melanoma cells secret secretory leukocyte protease inhibitor (SLPI) and elicit neurite outgrowth of nociceptors, which attenuate the cytotoxicity of CD8 + T cell via CGRP-RAMP1 axis (Fig. 5C) (72). In metastatic breast tumors, endothelium-derived Slit Homolog 2 (SLIT2) actively promote tumor sensory innervation, which release SP to cause cancer cell death, driving cancer invasion and metastasis (Fig. 5D) (81). Technological advances such as Trace-n-Seq now enable molecular profiling of tumor-innervating neurons at single-cell resolution, surpassing conventional scRNA-seq and may advance the drug target identification of neuro-stimulated carcinoma (82). Continued development of tools for deeper interrogation, quantification and imaging of tumor-infiltrated neuronal activity will also help to clarify the neuronal inputs affecting cancer biology. Immune cells modulate the neural system The long-held dogma envisioning the brain as an immune-privileged organ has undergone a paradigm shift. Emerging studies reveal that the brain is in proximate anatomically and physiologically communication with immune cells for proper development, normal function and homeostatic maintenance. Immune cells reside in specialized immunological niches in the brain (parenchyma, meninges, choroid plexus and the perivascular spaces) and regulate CNS function by direct interaction, cytokine signaling and cerebrospinal fluid flow (CSF) dynamics (83,84). Furthermore, the demonstration of the CNS lymphatic drainage and the skull microscopic channels linking bone marrow to CSF, establishes novel pathways for systemic neuroimmune communication (85,86). Tightly regulated neuroimmune interplay in the CNS is pivotal for the proper development and function of the brain, the perturbation of which underpins multiple neurological disorders (87–90). In this part, we’ll elaborate the recent advances in how innate and adaptive immune regulate neural system, while future exploration on the topic will offer novel perspective to design new therapeutic strategies for brain diseases. Innate immune cells The cross-talk between brain and innate immune cells is implicated in sculpting neural circuits, supporting neurodevelopment and maintaining functional brain homeostasis (87,91–94). A hallmark of developing CNS is overproduction followed by selective pruning, an activity-dependent program in which substantial inactive neurons, synapses and myelin are eliminated. Among innate immune cells, microglia—the primary resident macrophages of the CNS, have been the most extensively studied. Derived from the yolk sac, microglia exhibit peak diversity during embryogenesis and become relatively homogeneous in adulthood (92,95). Through developmentally regulated phagocytosis and trophic signaling, they contribute to essential processes such as neurogenesis, synaptic refinement and myelin elimination (96–98). During development, microglia eliminate surplus neurons through phagocytosis or via cytotoxicity mediated by reactive oxygen species and nerve growth factor (96,99). They further contribute to neural circuit refinement by spatially regulating synaptogenesis and synaptic pruning (97,100,101). To ensure the proper synaptic pruning without erroneous elimination, microglia exhibit spatiotemporal heterogeneity and integrate diverse cerebral signals from neurons and other cells (102–104). For instance, GABA released by inhibitory neurons triggers a pruning transcriptional program in GABAb-receptive microglia, leading to selective sculpting of inhibitory but not excitatory synapses (Fig. 6) (101). Similarly, astrocyte-derived IL-33 engages microglial ST2 to enhance phagocytosis, a mechanism temporally modulated to align with neurodevelopmental transitions (Fig. 6) (105,106). Non-phagocytic synaptic refinement occurs through interaction of Fn14 expressed on neurons and TWEAK released by microglia in a sensory experience-dependent manner (Fig. 6) (107). Conversely, immune checkpoint signals such as TGF-α and CD47 prevent excessive or inappropriate pruning, thereby synchronizing microglial activity with developmental requirements (108,109). Microglia also remove supernumerary myelin sheaths via activity-dependent microglia–oligodendrocyte crosstalk (98). Together, these mechanisms underscore the role of microglia in selectively eliminating less active components of the developing CNS—a process analogous to lymphocyte selection. In the adult brain, microglia serve as a dynamic sentinels, patrolling parenchyma with highly motile protrusions and switching to fighting state once encountered with threats (110). They could accommodate their morphology and function to the changing microenvironment, the dysregulation of which is tightly associated with neurodegeneral diseases and brain ageing (111–114). For instance, microglia clear myelin debris and promote oligodendrocyte progenitor maturation to facilitate remyelination after injury (115,116). They also regulate oligodendrocyte lipid metabolism via TGFβ/TGFβR axis to maintain myelin integrity (Fig. 6) (91). Beyond myelin health, microglia also modulate cognition function, brain activity and memory process (106,117–120). For instance, microglia are recruited by neuronal ATP, which they convert to adenosine to suppress hyperactivity (Fig. 6) (118). In parallel, microglia could also release Prostaglandin E2 to reduce striatal neuronal excitability, representing a complementary mechanism to inhibitory neurons for preventing pathological overactivation (119). Furthermore, experience-dependent neuronal IL-33 recruits microglia for extracellular matrix remodeling and memory consolidation, while C1q-dependent pruning dissociates engram cells and impairs remote memory (Fig. 6) (106,120). Taken together, one can envisage that the dysregulation of microglia-brain crosstalk could bring catastrophic repercussion to the CNS which underpins multiple neurological disorders and age-related cognitive decline (111–114). Natural killer (NK) cells and neutrophils also differentially modulate neuroimmune crosstalk under physiological and pathological contexts (121–125). In steady state, meningeal NK cells secret INF-γ which drives the expression of TRAIL in astrocytes to eliminate T cell, limiting neuroinflammation (123). Conversely, in the aged brain, NK cells activated by IL-27 eliminate senescent neuroblasts, impairing neurogenesis and cognitive function (122). These findings highlight the spatial and functional heterogeneity of NK cells and reflect the dynamism of brain-immune crosstalk. In comparison, neutrophils are primarily implicated in neurodegenerative pathology (121,124,125). In Alzheimer’s diseases, Aβ deposits-activated LFA-1 integrin facilitates the neutrophils adhesion to vascular endothelium and migration into brain parenchyma (124). Infiltrated neutrophils release neutrophil extracellular traps (NETs) and IL-17, which exacerbate blood-brain barrier disruption and neuronal injury, accelerating disease progression and cognitive decline (121,124). Furthermore, neutrophil adhesion in cerebral capillaries stalls cortical perfusion, compounding hypoperfusion and neurodegeneration (125). Innate-like lymphoid cells including γδ T cells and B1 cells, infiltrate the neonatal meninges and engage with neurons, glia, and oligodendrocyte precursor cells to modulate memory and behavior (94,126). Notably, a recent landmark study revealed that meningeal ILC2s enhance inhibitory synapse formation via IL-13 during early development, identifying a previously unrecognized therapeutic target for neurodevelopmental disorders (87). Together, these studies illustrate a spatiotemporally organized logic of neuroimmune regulation, wherein innate immune cells act as both guardians and disruptors of CNS integrity. Adaptive immune cells Unlike innate immune cells, adaptive immune cells populate the meninges later in postnatal development and maintain their number through self-renewal or recruitment of circulating lymphocytes (127). Adaptive lymphoid cells such as T cells and B cells are found to reside in the brain and modulate synaptic pruning, myelination and neuronal activity. For instance, CD4 + T cells are implicated in contextual fear memory by regulating the synaptic function of GABAergic neurons via IL-4 (128). Of note, the adaptive and innate immune compartments in the CNS are not isolated but intricately intertwined, adding another layer of complexity to the dynamic neuroimmune dialogue. In mice, brain residential CD4 + T cells are requisite for the maturation of microglia during fetal-to-adult transition which is requisite for synapses refinement (129). To date, regulatory T cells (Tregs) are one of the most extensively studied CD4 + T cells involved in the interaction with microglia, acting as important cerebro-protective immunomodulators under multiple pathological conditions (130). For instance, Tregs are recruited by chemokines CCL1 and CCL20 to the brain and secret amphiregulin to suppress neurotoxic astrogliosis (131). Meanwhile, CD4 + T cells also contribute to neurological diseases such like Lewy body dementia and maternal immune activation (MIA)-induced behavioral abnormalities in offspring (132–134). Compared to CD4 + T cells, CD8 + T cell in the CNS are often associated with neuropathology in conditions such as Alzheimer’s disease (135). During recovery from neurotropic flavivirus infection, IFN-γ produced by CD8 + T cells promotes microglia-mediated synaptic pruning and cognitive deficits (136). This CD8 + T cell-derived IFN-γ can also trigger neuronal CCL2 release, exacerbating microglia-driven synapse loss and neuronal injury in neuroinflammation (104). Furthermore, IFN-γ from CD8 + T cells contributes to the loss of OPCs and oligodendrocytes during inflammatory demyelination (137). Concurrently, early-developing B cells originating from skull hematopoietic stem cells reside in the meninges and undergo negative selection, the disruption of which is tightly associated with pathogenesis of multiple sclerosis (138). Besides the circulation-independent route, gut-derived IgA + plasma cells home to the meninges under homeostatic conditions, positioning near dural venous sinuses and defending CNS at this vulnerable barrier surface (139). In multiple sclerosis, CNS-infiltrating and meningeal B cells could secret IL-23, expanding the Th17 cell population and thereby promoting autoimmune inflammation (140). Taken together, it’s abundantly clear that the CNS has established immunological pathways to ensure the well-organized mobilization and function of immune cells in response to immunological cues in the brain. The neural control of immunity could in turn affect the appropriate development and proper function of the brain, the dysregulation of which is thereby considered as an escalating factor in neurological diseases and ageing. Conclusion The long-established assumption considering the brain as an immune-privileged organ has undergone a paradigm shift as contemporary research reveals extensive bidirectional communication between the nervous and immune systems. In this review, we have presented the recent advances unmasking the well-characterized mechanisms by which the nervous and immune system regulate and shape each other. Modulating organogenesis and plasticity during development and homeostasis, neural system plays a pivotal role in regulating immune system during homeostasis, host-defense, inflammation and cancer. Multifarious immune cells express receptors for various neurotransmitters, neuropeptides and neuronal hormones. Upon stimulation by endogenous and exogenous cues, the nervous system could directly regulate immune responses by releasing diverse signaling molecules. The widely-distributed neural system could transmit the signal on a timescale of milliseconds, enabling an extended physiological reach and accelerated reaction speed of immune system. Given that neural system actively regulates the immune responses in multiple organs and tissues, harnessing neuronal responses via methods like chemogenetics and optogenetics could offer therapeutic effects with enhanced curative efficiency. Meanwhile, innate and adaptive immune cells could exert profound influence on brain throughout the lifetime from embryogenesis to ageing, contributing to the proper development and functional maintenance of the brain. Immune cells reside in the specialized niches including brain parenchyma, meninges, choroid plexus and the perivascular spaces, modulating processes like synaptic pruning, myelination and neuronal survival. Disturbance of the delicate neuroimmune balance is implicated in multiple neurological disorders like Alzheimer’s diseases, Parkinson’s diseases and multiple sclerosis. The future work exploring the brain immunity in the homeostatic and pathological context will continue to extend our knowledge in this field and reveal therapeutic strategies for treating various neurological disorder. Furthermore, these two systems also share substantial properties including sensing, reacting and memory. Multifarious signaling molecules and pathways are conserved among immune cells and brain-resident cells, exerting distinctive functions. Future work rooting out more shared signaling molecules and pathways and probing into the mechanistic similarities and differences of neuronal and immune responses like memory will continue to yield important insights, offering a wide range of novel opportunities for the design of therapeutic approaches and drug-delivery strategies. Author Contributions WH conceptualized the review topic, designed the framework, performed the literature review, wrote the original draft and designed figures. YC and XW contributed to critical revisions and offered valuable guidance. All authors approved the final version. Acknowledgements We would like to express our sincere gratitude to all those who contributed to this work but do not meet the criteria for authorship. Specifically, we thank Yuhao Zheng, Lisi Zhu for their valuable assistance in language editing. We also appreciate the insightful comments and suggestions from Jingxuan Shao, Jiawei Song and Wenle Zhou which helped improve the quality of this manuscript. Finally, we extend our thanks to the reviewers and editors for their constructive feedback. Funding This work was supported by the National Natural Science Foundation of China (no. 82271866, 82471853 and 8240062935), Guangdong Basic and Applied Basic Research Foundation (no. 2024B1515020039). Data Availability No data were generated or analyzed during the current study. Competing Interests The authors declare no competing financial interests. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. References 1. Medawar PB. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol 1948; 29 :58–69.2. 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The sensory nervous system is subdivided into somatic (innervates skin and soft tissues) and visceral arms (innervates visceral organs) while autonomic nervous system is further divided into sympathetic, parasympathetic and enteric nervous system. (B) The cell body of sensory neuron reside within ganglia and their nerve terminals innervate barrier tissues. (C) Parasympathetic, sympathetic nervous system and the enteric nervous system (ENS) work antagonistically to regulate body response. Fig. 2. Neuro-immune crosstalk in tissues under steady state. Enteric nervous system (ENS)-derived vasoactive intestinal polypeptide (VIP) regulates ILC3 responses and food uptake via VPAC2 and promotes IL-5 release from ILC2s to maintain eosinophil homeostasis. Muscularis macrophages (MMs) secrete bone morphogenetic protein 2 (BMP2) to activate enteric neurons, which feedback colony stimulatory factor 1 (CSF1) to sustain MMs development. TGF-β released by enteric neurons maintains neurosupportive phenotype of MMs which are refine ENS in early life. Calcitonin gene relating peptide (CGRP) and stance P (SP) released by Nav 1.8 + neuron induce the mucus secretion of goblet cells, while Ach from cholinergic neurons maintains epithelial barrier integrity. (B) Gut sympathetic neuron-derived norepinephrine (NE) promotes ILC2 migration to the pancreas, where IL-5/IL-13 stimulate glucagon secretion from pancreatic α-cell. In adipose tissue, sympathetic neuorn-derived NE promote release of glial cell line-derived neurotrophic factor (GDNF) by mesenchymal cell to boost ILC2s-mediated energy expenditure. (C) In the skin, CGRP induces macrophage M2 polarization, reduces neutrophil infiltration, and activates dermal dendritic cells (dDCs) to release IL-23 critical for γδ T cell-mediated IL-17/IL-22 production. GINIP + neurons-released TAFA4 also induces macrophage M2 polarization requisite for tissue repair while Langerhans cell-dependent Mrgprd + neurons suppress Mrgbr2 expression of mast cell via glutamate signaling. Fig. 3. Tissue-specific neuroimmune axes in host-defense against microbes across skin, lung, and gut. In the skin, Staphylococcus aureus (S. aureus) serine V8 protease activate the pruriceptors via protease-activated receptor 1 (PAR1) to elicit itch, while the its NFP and α-HL induce pain via formyl peptide receptors (FPRs) and ADAM10, respectively. Nociceptors-derived CGRP then suppresses neutrophils infiltration and TNF-α production by macrophages. Streptococcus pyogenes (S. pyogenes) secret streptolyisn S to activate TRPV1 + neurons, releasing CGRP to inhibit neutrophil recruitment and phagocytosis. In contract, during cutaneous candida albicans (C. albicans) infection, TRPV1 + neurons-derived CGRP drives the IL-23 production by CD301 + dDCs, enabling γδ T cell-mediated antifungal immunity. (B) In the lung, mycobacterium tuberculosis (Mtb) produces sulfolipid 1 (SL-1) and activate TRPV1 + neurons to trigger cough. During S. aureus and K. pneumoniae infection, TRPV1 + nociceptors can secret CGRP to suppress host immunity. (C) In the gut, the ENS-derived IL-18 critically induces antimicrobial protein (AMP) synthesis in goblet cells to defend against Salmonella infection. In parallel, commensal-activated Nav1.8 + neurons enhance mucus secretion via CGRP-RAMP1 signaling, while nociceptor-derived CGRP concurrently reduces microfold cells (M cells) density and sustains segmented filamentous bacteria (SFB) colonization to fortify barrier immunity. Gut extrinsic sympathetic neurons-derived NE polarizes muscularis macrophages (MMs) toward M2-like tissue-protective phenotype via beta-2 adrenergic receptor (β2AR). For ILC2 regulation, enteric neurons sense ILC2-derived IL-13 through IL-13R, forming a CGRP-mediated negative feedback loop that constrains anti-helminth immunity, while sympathetic β2AR signaling further suppresses ILC2 activity. Conversely, cholinergic neuron-derived neuropeptide neuromedin U (NMU) potently activates ILC2s and recruits eosinophils, driving goblet cell differentiation and accelerating helminth expulsion. Fig. 4. Neuropeptide-mediated bidirectional control of inflammation. sensory neurons-derived CGRP exacerbates type 17 immunity while inhibiting type 2 responses. Paradoxically, CGRP secreted by pulmonary neuroendocrine cells (PNEC) amplifies type 2 inflammation. Neuromedin U (NMU) promotes type 2 inflammation via neuromedin U receptor 1 (NMR1) on type 2 innate lymphoid cell (ILC2s) and eosinophils. (C) Stance P (SP) drives cutaneous type 2 responses via mast cells, CD301b + dendritic cells (DCs) and ILC2s while preserving gut microbiome homeostasis. And Vasoactive intestinal polypeptide (VIP) promotes type 2 inflammation via VIP receptor type 2 (VPAC2) expressed on Th2 and ILC2s. (C) Norepinephrine (NE) suppresses ILC2-driven type 2 inflammation via β2AR but paradoxically amplifies hypersensitivity via NE-Ach circuits. Dopamine promotes Th2 responses via DRD4 whereas suppressing ILC2 and macrophages responses via DRD1. Fig. 5. Neuronal control of tumor progression in glioma, gastric, melanoma and breast cancer. In glioma, neuron-derived glutamine elicits glioma cell depolarization and promote tumor growth via α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and NMDA N-methyl-D-aspartic acid (NMDA) receptor. Neuronal BDNF acts on TrkB receptor to promote the transportation of AMPA receptor and regulate the neuron-cancer cell synaptic plasticity. Neurons also release neuroligin-3 and insulin growth factor 1 (IGF1) to promote tumor progression and metastasis. In turn, cancer cell remodels the synaptic plasticity through thrombosponsin-1 to facilitate its progression. B. In gastric cancer, cancer cell secret nerve growth factor (NGF) to act on TrkA receptor and induce the release of CGRP by nociceptor, which promote tumor progression via RAMP1. C. Melanoma cell-derived secretory leukocyte protease inhibitor (SLPI) elicits elicit neurite outgrowth of nociceptors, which attenuate the cytotoxicity of CD8 + T cell via CGRP-RAMP1 axis. D. In breast cancer, endothelium-derived Slit Homolog 2 (SLIT2) promote tumor sensory innervation, which release SP to cause TACR1 high cancer cell death, driving cancer invasion and metastasis via ssRNA/TLR7 signaling. Fig. 6. Dialogue between microglia, neurons, astrocytes and oligodendrocytes contributes to synapse refinement, synaptic plasticity, neuronal activity and myelin health. Inhibitory neurons-derived GABA induce inhibitory synapse pruning by GABAb-receptive microglia, while astrocyte-derived IL-33 could bind to ST2 expressed on microglia to fuel phagocytosis function. Non-phagocytic synaptic refinement occurs through interaction of Fn14 expressed on thalamic relay neurons and TWEAK released by microglia. Microglia orchestrate myelin health by regulating the lipid metabolism of oligodendrocyte via TGFβ/TGFβR axis, preventing hypermyelination or demyelination of the already existed myelin. ATP released by activated neurons recruits microglia to catalyze ATP to adenosine, thereby suppressing hyperactivity. In addition, neuronal IL-33 expressed in an experience-dependent manner recruits microglia for extracellular matrix remodeling, enhancing synaptic plasticity and memory consolidation. Information & Authors Information Version history V1 Version 1 07 October 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords allergy treament basic immunology clinical immunology mucosal immunity Authors Affiliations Wenqian Huang Sun Yat-sen University Zhongshan School of Medicine View all articles by this author Xiangyang Wang Southern Medical University School of Laboratory Medicine and Biotechnology View all articles by this author Yingjiao Cao 0009-0004-9367-9792 [email protected] Sun Yat-sen University Zhongshan School of Medicine View all articles by this author Metrics & Citations Metrics Article Usage 180 views 153 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Wenqian Huang, Xiangyang Wang, Yingjiao Cao. The bidirectional neuroimmune dialogue in inter-organs. Authorea . 07 October 2025. DOI: https://doi.org/10.22541/au.175983149.90056770/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. 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