1. GPR41 deficiency aggravates type 1 diabetes in streptozotocin-treated mice by promoting dendritic cell maturation.
- Author
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Li JH, Zhang M, Zhang ZD, Pan XH, Pan LL, and Sun J
- Subjects
- Animals, Mice, Mice, Inbred C57BL, STAT3 Transcription Factor metabolism, Suppressor of Cytokine Signaling 3 Protein metabolism, Suppressor of Cytokine Signaling 3 Protein genetics, Interferon-gamma metabolism, Pancreas metabolism, Pancreas pathology, Pancreas immunology, Male, Female, Gastrointestinal Microbiome, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 metabolism, Receptors, G-Protein-Coupled deficiency, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Dendritic Cells immunology, Dendritic Cells metabolism, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Experimental immunology, Streptozocin, Mice, Knockout, Mice, Inbred NOD
- Abstract
Disturbances in intestinal immune homeostasis predispose susceptible individuals to type 1 diabetes (T1D). G-protein-coupled receptor 41 (GPR41) is a receptor for short-chain fatty acids (SCFAs) mainly produced by gut microbiota, which plays key roles in maintaining intestinal homeostasis. In this study, we investigated the role of GPR41 in the progression of T1D. In non-obese diabetic (NOD) mice, we found that aberrant reduction of GPR41 expression in the pancreas and colons was associated with the development of T1D. GPR41-deficient (Gpr41
-/- ) mice displayed significantly exacerbated streptozotocin (STZ)-induced T1D compared to wild-type mice. Furthermore, Gpr41-/- mice showed enhanced gut immune dysregulation and increased migration of gut-primed IFN-γ+ T cells to the pancreas. In bone marrow-derived dendritic cells from Gpr41-/- mice, the expression of suppressor of cytokine signaling 3 (SOCS) was significantly inhibited, while the phosphorylation of STAT3 was significantly increased, thus promoting dendritic cell (DC) maturation. Furthermore, adoptive transfer of bone marrow-derived dendritic cells (BMDC) from Gpr41-/- mice accelerated T1D in irradiated NOD mice. We conclude that GPR41 is essential for maintaining intestinal and pancreatic immune homeostasis and acts as a negative regulator of DC maturation in T1D. GPR41 may be a potential therapeutic target for T1D., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)- Published
- 2024
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