Metabolite - sensing receptor Ffar2 regulates colonic group 3 innate lymphoid cells and gut immunity

Group 3 innate lymphoid cells (ILC3s) sense environmental signals that are critical for gut homeostasis and host defense. However, the metabolite-sensing G-protein-coupled receptors that regulate colonic ILC3s remain poorly understood. We found that colonic ILC3s expressed Ffar2, a microbial metabolite-sensing receptor, and that Ffar2 agonism promoted ILC3 expansion and function. Deletion of Ffar2 in ILC3s decreased their in situ proliferation and ILC3-derived IL-22 production. This led to impaired gut epithelial function characterized by altered mucus-associated proteins and antimicrobial peptides and increased susceptibility to colonic injury and bacterial infection. Ffar2 increased IL-22+ CCR6+ ILC3s and influenced ILC3 abundance in colonic lymphoid tissues. Ffar2 agonism differentially activated AKT or ERK signaling and increased ILC3-derived IL-22 via an AKT and STAT3 axis. Our findings demonstrate that Ffar2 regulates colonic ILC3 proliferation and function in a cell-intrinsic manner and identifies an ILC3-receptor signaling pathway regulating gut inflammatory tone and pathogen defense. Colonic ILC3s (CD45+Lin- CD90.2+ NK1.1- NKp46+/- KLRG1-) were sorted from Ffar2-/- mice and littermate control WT mice. Two independent RNA-seq experiments were performed. (i.e. two biological replicates (sex-matched) for each group that contained RNA from pooled colonic ILC3s from 10 to 15 mice). BioProject accession: PRJNA547949, SRA Study accession: SRP201015 Please note that the processed data files have been updated on Mar 12, 2020.