Role of Nutrient-sensing Receptor GPRC6A in Regulating Colonic Group 3 Innate Lymphoid Cells and Inflamed Mucosal Healing.

Abstract

BACKGROUND AND AIMS:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Qihang Hou, Jingxi Huang, Xia Xiong, Yuming Guo, Bingkun Zhang
• Journal: Journal of Crohn's & colitis (J Crohns Colitis) Vol. 16 Issue 8 Pg. 1293-1305 (Aug 30 2022) ISSN: 1876-4479 [Electronic] England
• PMID: 35134872 (Publication Type: Journal Article)
• Copyright: © 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: [email protected].

Chemical References

• GPRC6A protein, mouse
• Receptors, G-Protein-Coupled
• Arginine

Topics

• Animals
• Arginine (metabolism)
• Colitis
• Immunity, Innate
• Intestinal Mucosa
• Lymphocytes (metabolism)
• Mammals
• Mice
• Nutrients
• Receptors, G-Protein-Coupled (metabolism)