Epithelial cell intrinsic IL-1R signaling regulates intestinal homeostasis and inflammation

Abstract

Abstract Intestinal epithelial cells (IECs) provide a critical first line of defense against microbes through barrier function, production of antimicrobial peptides (AMPs), secretion of cytokines, and recruitment of inflammatory cells. Whether single or multiple upstream cues regulate this diverse set of responses from IECs is not clear. Here we discover an unexpected role for Interleukin-1 Receptor (IL-1R) signaling in IECs in regulating intestinal homeostasis and inflammation. Specifically, absence of IL-1R in epithelial cells abrogates a homeostatic anti-microbial program including production of AMPs. Although IL-1R signaling alone is not sufficient to drive the AMP gene induction in IECs, the IL-22-driven anti-microbial program requires synergistic IL-1R signaling. Mechanistically, IL-1R signaling results in enhancement and temporal stabilization of STAT3 phosphorylation downstream of IL-22R. Thus, we reveal an unexpected cooperation between IL-1R and IL-22R in directly regulating an intestinal anti-microbial program. In contrast, absence of IL-1R in IECs protects mice from chemically-induced acute intestinal inflammation suggesting that IEC specific IL-1R signaling contributes to inflammation and pathology. We find that IL-1R signaling directly induces expression of chemokines as well as genes involved in the production of reactive oxygen species in IECs, a process that likely evolved to protect against enteric pathogens. Our findings establish a critical role for IEC specific IL-1R signaling in both steady state anti-microbial gene induction as well as intestinal inflammation. Further studies are likely to reveal potential targets for developing therapies against Crohn’s Disease and Ulcerative Colitis.