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.
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Acknowledgements
The study was supported by funds from the National Natural Science Foundation of China (Grant Nos. 82122068 and 82070666), the Fundamental Research Funds for the Central Universities (Grant No. JUSRP121009), the Natural Science Foundation of Jiangsu Province (Grant Nos. BK20200016 and BK20221086, China), the Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, the Jiangsu Funding Program for Excellent Postdoctoral Talent (Grant No. 2022ZB484), the top medical expert team of Wuxi Taihu Talent Plan (Grant Nos. DJTD202106 and GDTD202105), the Medical Key Discipline Program of Wuxi Health Commission (Grant Nos. ZDXK2021007 and CXTD2021005), the Scientific Research Program of Wuxi Health Commission (Grant Nos. Z202109 and M202208), and the Wuxi Science and Technology Development Fund (Grant No. Y20222001).
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JS and LLP designed and interpreted experiments. JHL, MZ, and ZDZ performed experiments and analyzed data. JHL, ZDZ, and XHP drafted the manuscript. JS and LLP critically reviewed the manuscript. All authors approved the final manuscript.
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Li, Jh., Zhang, M., Zhang, Zd. et al. GPR41 deficiency aggravates type 1 diabetes in streptozotocin-treated mice by promoting dendritic cell maturation. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01242-7
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DOI: https://doi.org/10.1038/s41401-024-01242-7