Abstract
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.
Published Version
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