State Key Laboratory of Animal Nutrition, Department of Animal Nutrition & Feed Science, College of Animal Science & Technology, China Agricultural University, Haidian District, Beijing 100193, China.
Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China.
J Crohns Colitis. 2022 Aug 30;16(8):1293-1305. doi: 10.1093/ecco-jcc/jjac020.
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.
第三组先天淋巴细胞（ILC3）感知环境信号，在肠道稳态和免疫防御中起关键作用。G 蛋白偶联受体（GPCR）介导细胞对各种环境信号的反应。然而，GPCR 对 ILC3 的调节机制在很大程度上尚不清楚。
我们使用野生型（WT）和 GPRC6A-/-小鼠来研究 GPRC6A 在 ILC3 群体和功能中的作用。然后我们从 WT 和 GPRC6A-/-小鼠中纯化 ILC3。通过给予葡聚糖硫酸钠（DSS）或 C. rodentium 感染诱导 WT 小鼠和 GPRC6A-/-小鼠结肠炎。此外，将选择性 GPRC6A 激动剂 L-精氨酸给予结肠炎小鼠。
我们发现结肠 ILC3 表达 GPRC6A。GPRC6A 缺失减少了 ILC3 衍生的白细胞介素 22（IL-22）产生和增殖 ILC3 的数量，导致对结肠损伤和病原体感染的易感性增加，并损害炎症性粘膜愈合。进一步的研究表明，GPRC6A 激动剂 L-精氨酸通过体外哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）信号促进结肠 ILC3 的扩增和功能。此外，L-精氨酸在体内减轻 DSS 诱导的结肠炎。这与 ILC3 分泌的 IL-22 显著增加有关。
我们的研究结果揭示了营养感应受体 GPRC6A 在结肠 ILC3 功能中的作用，并确定了一种调节炎症性粘膜愈合的新型 ILC3 受体信号通路。
