Sirtuin 1 regulates the phenotype and functions of dendritic cells through Ido1 pathway in obesity.

Sirtuin 1 regulates the phenotype and functions of dendritic cells through Ido1 pathway in obesity. | 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 Sirtuin 1 regulates the phenotype and functions of dendritic cells through Ido1 pathway in obesity. Niels Olsen Saraiva Camara, Jean De Lima, Jefferson Leite, Paulo José Basso, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4480505/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Oct, 2024 Read the published version in Cell Death & Disease → Version 1 posted 12 You are reading this latest preprint version Abstract Sirtuin 1 (SIRT1) is a class III histone deacetylase (HDAC3) that plays a crucial role in regulating the activation and differentiation of dendritic cells (DCs) as well as controlling the polarization and activation of T cells. Obesity, a chronic inflammatory condition, is characterized by the activation of immune cells in various tissues. We hypothesized that SIRT1 might influence the phenotype and functions of DCs through the Ido1 pathway, ultimately leading to the polarization towards proinflammatory T cells in obesity. In our study, we observed that SIRT1 activity was reduced in bone marrow-derived DCs (BMDCs) from obese animals. These BMDCs exhibited diminished oxidative phosphorylation (OXPHOS) and increased extracellular acidification rates (ECAR), along with enhanced expression of class II MHC, CD86, and CD40, and elevated secretion of IL-12p40, while the production of TGF-β was reduced. The kynurenine pathway activity was decreased in BMDCs from obese animals, particularly under SIRT1 inhibition. SIRT1 positively regulated the expression of Ido1 in DCs in a PPARγ-dependent manner. To support these findings, ATAC-seq analysis revealed that BMDCs from obese mice had differentially regulated open chromatin regions compared to those from lean mice, with reduced chromatin accessibility at the Sirt1 genomic locus in BMDCs from obese WT mice. Gene Ontology (GO) enrichment analysis indicated that BMDCs from obese animals had disrupted metabolic pathways, including those related to GTPase activity and insulin response. Differential expression analysis showed reduced levels of Pparg and Sirt1 in BMDCs from obese mice. This study highlights that SIRT1 controls the metabolism and functions of DCs through modulation of the kynurenine pathway and Ido1, with significant implications for obesity-related inflammation. Biological sciences/Immunology/Antigen processing and presentation/Antigen-presenting cells Biological sciences/Immunology/Innate immune cells/Dendritic cells Sirtuin 1 Indoleamine 2 3 dioxygenase Dendritic cell Obesity. Full Text Additional Declarations (Not answered) Cite Share Download PDF Status: Published Journal Publication published 18 Oct, 2024 Read the published version in Cell Death & Disease → Version 1 posted Editorial decision: revise 02 Jul, 2024 Review # 4 received at journal 01 Jul, 2024 Review # 2 received at journal 27 Jun, 2024 Reviewer # 4 agreed at journal 25 Jun, 2024 Reviewer # 3 agreed at journal 23 Jun, 2024 Reviewer # 2 agreed at journal 09 Jun, 2024 Reviewer # 1 agreed at journal 08 Jun, 2024 Reviewers invited by journal 06 Jun, 2024 Submission checks completed at journal 03 Jun, 2024 First submitted to journal 31 May, 2024 Unknown event 28 May, 2024 Editor assigned by journal 26 May, 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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Obesity, a chronic inflammatory condition, is characterized by the activation of immune cells in various tissues. We hypothesized that SIRT1 might influence the phenotype and functions of DCs through the Ido1 pathway, ultimately leading to the polarization towards proinflammatory T cells in obesity. In our study, we observed that SIRT1 activity was reduced in bone marrow-derived DCs (BMDCs) from obese animals. These BMDCs exhibited diminished oxidative phosphorylation (OXPHOS) and increased extracellular acidification rates (ECAR), along with enhanced expression of class II MHC, CD86, and CD40, and elevated secretion of IL-12p40, while the production of TGF-β was reduced. The kynurenine pathway activity was decreased in BMDCs from obese animals, particularly under SIRT1 inhibition. SIRT1 positively regulated the expression of Ido1 in DCs in a PPARγ-dependent manner. 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