Metabolite-Sensing Receptor Ffar2 Regulates Colonic Group 3 Innate Lymphoid Cells and Gut Immunity

Abstract

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. Deficiency of Ffar2 in ILC3s decreased their in situ proliferation and ILC3-derived interleukin-22 (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 suggest that Ffar2 regulates colonic ILC3 proliferation and function, and they identify an ILC3-receptor signaling pathway modulating gut homeostasis and pathogen defense.

RETRACTED: Living with Yourself: Innate Lymphoid Cell Immunometabolism

“…The microbiota can also indirectly influence levels of indole 3-aldehyde, a tryptophan-derivative that binds to AHR, to promote IL-22 production by ILC3s [83]. Furthermore, signaling of microbiota-derived short-chain fatty acid (SCFA) via free fatty acid receptor 2 (FFAR2) can induce colonic ILC3 proliferation and production of IL-22 to promote intestinal barrier immunity [84] while ILC2s are inhibited by the SCFA butyrate, leading to improvement of allergic asthma symptoms [85]. ILC3s may be unique in their dependence on microbiota-derived metabolites, because NK and ILC2 development is not perturbed while NKp46 + ILC3s can be reduced in germfree mice [25,86,87].…”

Strategies to Dissect Host-Microbial Immune Interactions That Determine Mucosal Homeostasis vs. Intestinal Inflammation in Gnotobiotic Mice

“…Tregs were not induced in Ffar −/− mice or in cells from these KO mice by in vivo or ex vivo exposure to propionate. Interestingly, acetate and propionate also stimulate colonic ILC3 proliferation, accumulation and IL-22 production in a Ffar2-dependent manner (60). Likewise, Tyagi et al (61) stimulated numbers of FoxP3 + Tregs in small intestine Peyer's patches with butyrate.…”

Immunoregulatory Sensory Circuits in Group 3 Innate Lymphoid Cell (ILC3) Function and Tissue Homeostasis

“…The SCFA receptor GPR109a was implicated in the microbiota-associated regulation of ILC3 cytokine production via the modulation of dendritic cell (DC)-derived IL-23 in the colon, although these studies largely utilized a GPR109a agonist-leaving the precise contribution of endogenous SCFA unclear (45). Interestingly, a recent study highlighted ILC3-intrinsic expression of the SCFA receptor Gpr43 (Ffar2) in the modulation of intestinal ILC3 responses (Figure 1: inputs) (46). Triggering of GPR43 with the SCFAs propionate and acetate (but not butyrate) selectively promoted colonic ILC3 proliferation and expansion and production of IL-22, subsequently protecting mice from chemically induced colitis and from enteric bacterial infection (46).…”

“…Interestingly, a recent study highlighted ILC3-intrinsic expression of the SCFA receptor Gpr43 (Ffar2) in the modulation of intestinal ILC3 responses (Figure 1: inputs) (46). Triggering of GPR43 with the SCFAs propionate and acetate (but not butyrate) selectively promoted colonic ILC3 proliferation and expansion and production of IL-22, subsequently protecting mice from chemically induced colitis and from enteric bacterial infection (46).…”