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    Group 3 innate lymphoid cells [ILC3s] sense environmental signals and are critical in gut homeostasis and immune defence. G-protein-coupled receptors [GPCRs] mediate cellular responses to diverse environmental signals. However, the GPCRs' regulation mechanisms of ILC3s is largely unknown. We used wild-type [WT] and GPRC6A-/- mice to investigate the role of GPRC6A in the population and the function of ILC3s. We then purified ILC3s from WT and GPRC6A-/- mice. Colitis was induced in WT mice and GPRC6A-/- mice through dextran sodium sulphate [DSS] administration or C. rodentium infection. Furthermore L-arginine, a selective GPRC6A agonist, was administered to mice with colitis. We found that colonic ILC3s expressed GPRC6A. The deficiency of GPRC6A decreased ILC3-derived interleukin-22 [IL-22] production and the number of proliferating ILC3s, which led to increased susceptibility to colon injury and pathogen infection and impaired inflamed mucosal healing. Further studies showed that L-arginine, a GPRC6A agonist, promoted colonic ILC3 expansion and function via the mammalian target of rapamycin complex 1 [mTORC1] signalling in vitro. In addition, L-arginine attenuated DSS-induced colitis in vivo. This was associated with a significant increase in IL-22 secretion by ILC3s. Our findings unveil a role for the nutrient-sensing receptor GPRC6A in colonic ILC3 function and identify a novel ILC3 receptor signalling pathway modulating inflamed mucosal healing. © The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email:


    Qihang Hou, Jingxi Huang, Xia Xiong, Yuming Guo, Bingkun Zhang. Role of Nutrient-sensing Receptor GPRC6A in Regulating Colonic Group 3 Innate Lymphoid Cells and Inflamed Mucosal Healing. Journal of Crohn's & colitis. 2022 Aug 30;16(8):1293-1305

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    PMID: 35134872

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