GPR109a Regulates Phenotypic and Functional Alterations in Macrophages and the Progression of Type 1 Diabetes

• Published in: Molecular nutrition & food research 2022-12, Vol.66 (23), p.e2200300-n/a
• Main Authors: Zhang, Zhaodi, Li, Jiahong, Zhang, Ming, Li, Binbin, Pan, XiaoHua, Dong, Xiaoliang, Pan, Li‐Long, Sun, Jia
• Format: Article
• Language: English
• Subjects: Adoptive transfer; Animals; butyrate; Cell activation; Cytokines; Cytotoxicity; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diet; Fermentation; G‐protein‐coupled receptor 109a; Homeostasis; Immune system; Intestinal microflora; Intestine; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - metabolism; Metabolites; Mice; Microorganisms; Polarization; Receptors; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Nicotinic - metabolism; Signal transduction; Signaling; SOCS-3 protein; Streptozocin; type 1 cytotoxic T cell; type 1 diabetes
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.202200300

Scope Dietary fibers can alter gut microbiota and microbial metabolite profiles. SCFAs are produced by bacterial fermentation of fiber, mediating immune homeostasis through G‐protein‐coupled receptors (GPCRs). GPR109a, a receptor for niacin and butyrate, expressed by immune cells and non‐immune cells, is a key factor regulating immune responses. However, the role and underlying mechanisms of GPR109a in type 1 diabetes (T1D) remain unclear. Methods and results Experimental T1D was induced by streptozotocin in GPR109a‐deficient (Gpr109a−/−) and wild type mice. The study found that Gpr109a−/− mice were more susceptible to T1D with dysregulated immune responses, along with increased M1 macrophage polarization (from 10.55% to 21.48%). Further, an adoptive transfer experiment demonstrated that GPR109a‐deficient macrophages promoted the homing of intestine‐derived type 1 cytotoxic T cells to pancreas (from 18.91% to 24.24%), thus disturbing the pancreatic immune homeostasis in non‐obese diabetic mice. Mechanistically, GPR109a deficiency promoted M1 macrophage polarization associated with the activation of suppressor of cytokine signaling 3‐signal transducer and activator of transcription 1 signaling pathway. Conclusion The findings reveal that macrophage GPR109a deficiency accelerates the development of T1D. Activation of GPR109a on macrophage by dietary components may provide a new strategy for preventing or treating T1D. Schematic diagram of the immunomodulatory effect of GPR109A on T1D. GPR109A deficiency promotes macrophage polarization toward pro‐inflammatory M1 macrophages, which may be related to SOCS3‐STAT1 signaling pathway, leading to homing of Tc1 cells from intestine to pancreas, thus aggravating T1D.