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GPR41 deficiency aggravates type 1 diabetes in streptozotocin-treated mice by promoting dendritic cell maturation

Acta Pharmacologica Sinica (2024)Cite this article

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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Fig. 1: The expression of GPR41 is decreased during T1D development.
Fig. 2: GPR41 deficiency aggravates T1D development in STZ-induced diabetes.
Fig. 3: GPR41 deficiency aggravates intestinal immune dysfunction.
Fig. 4: GPR41 deficiency disrupts the immune balance in the pancreas.
Fig. 5: GPR41 deficiency promotes the migration of intestinal effector CD8+ T cells to the pancreas.
Fig. 6: GPR41-deficient DCs aggravate pancreatic immune imbalance in NOD mice.
Fig. 7: GPR41 deficiency induces DC maturation by SOCS3/STAT3 signaling.
Fig. 8: Graphical summary for the role and mechanism of GPR41 deficiency in mediating the development of T1D in mice.

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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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Authors and Affiliations

  1. Department of Pediatric Laboratory, Affiliated Children’s Hospital of Jiangnan University (Wuxi Children’s Hospital), Jiangnan University, Wuxi, 214023, China

    Jia-hong Li & Li-long Pan

  2. Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China

    Jia-hong Li & Li-long Pan

  3. State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, 214122, China

    Ming Zhang, Zhao-di Zhang, Xiao-hua Pan & Jia Sun

  4. School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China

    Ming Zhang, Zhao-di Zhang, Xiao-hua Pan & Jia Sun

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Contributions

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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Correspondence to Li-long Pan or Jia Sun.

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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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