IL-22RA1 signaling regulates intestinal secretory cell development and protects against infectious colitis

Abstract

Abstract The gastrointestinal tract harbors a complex immune system to contend with both normal flora and invasive pathogens. Recently, interleukin (IL)-22 signaling has proven to play a critical role in maintaining the gut barrier, promoting epithelial healing and controlling inflammation from attaching and effacing pathogens. Specifically, IL-22 produced by Th17 cells and group 3 innate lymphoid cells (ILCs) is critical for host resistance to the attaching and effacing gut pathogen Citrobacter rodentium. However, the importance of intestinal epithelial IL-22Ra1 signaling in regulating secretory cell development and protecting against infectious colitis remains unknown. We hypothesize that intestinal IL-22 signaling plays an important role in mucosal host defense against infectious colitis by regulating the intestinal cell types that maintain the gut barrier. To test this hypothesis, we generated mice that selectively lack the receptor for IL-22, IL-22RA1, and discovered these mice have a striking phenotype of intestinal cell differentiation. We demonstrate that abrogation of intestinal IL-22 signaling led to a decreased number of goblet and paneth cells and decreased expression of the antimicrobial peptide Reg3g. Further, the IL-22RA1 intestinal specific knock-out mice were more susceptible to C. rodentium colitis than WT mice as demonstrated by increased weight loss that correlated with increased spleen bacterial burden, decreased epithelial cell proliferation and disrupted mucosal architecture. These findings offer insights into the protective role that IL-22 plays on mediating intestinal mucosal host defense and how critical IL-22 signaling is to intestinal cell differentiation and attenuating infectious colitis.