Gpr109a limits microbiota-induced IL-23 production to constrain ILC3-mediated colonic inflammation and carcinogenesis.

Abstract

Abstract A set of coordinated interactions between gut microbiota and the immune cells surveilling the intestine play a key role in shaping local immune responses and intestinal health. There are several immunoregulatory mechanisms in place that prevent the needless activation of immune cells against harmless gut bacteria. The dysregulation of interleukin-23 (IL-23) plays a critical role in the induction of several inflammatory diseases including inflammatory bowel disease (IBD). However, the molecular mechanisms regulating IL-23 production are poorly characterized. Gpr109a is a G-protein coupled receptor that is expressed at a very high level on innate immune cells and has been previously shown to play a key role in the induction of colonic Tregs. We show that Gpr109a−/−Rag1−/− mice exhibit spontaneous rectal prolapse and colonic inflammation, as characterized by the presence of an elevated number of IL-17-producing Rorγt+ innate lymphoid cells (ILC3). The genetic deletion of Rorγt ameliorated the spontaneous colonic inflammation in Gpr109a−/−Rag1−/− mice. Gpr109a-deficient colonic dendritic cells promote ILC3 by producing higher amounts of IL-23. Antibiotics treatment to deplete gut microbiota decreased IL-23 production, ILC3, and colonic inflammation in Gpr109a−/−Rag1−/− mice. Administration of niacin, a Gpr109a agonist, suppressed both IL-23 production by colonic DCs and ILC3 count in a Gpr109a-dependent manner. Collectively, our data presents a model suggesting that targeting Gpr109a will be potentially beneficial in the suppression of IL-23 mediated immunopathologies.