Mast Cells Play a Protective Role in Spontaneous Colitis

Abstract

Abstract Mast cells are modulators of inflammation and are activated during inflammatory bowel disease (IBD). Previous work has demonstrated that mast cells are proinflammatory in acute models of chemical colitis. However, the role of mast cells in chronic, spontaneous IBD models remains to be fully defined. We hypothesized that mast cells play a protective role in chronic, spontaneous colitis. We compared colitis and intestinal barrier function in IL10−/− mice to mast cell-deficient, colitis prone mice (double knockout (DKO): IL-10−/− x KitWsh/Wsh). Systemic engraftment of DKO mice with mast cells was performed. Mast cell-deficient DKO mice exhibited more severe colitis compared to mice that lacked IL-10 alone, indicated by increased colitis scores, mucosal hypertrophy, increased intestinal permeability, and spontaneous colonic cytokine production. Reconstitution of DKO mice with mast cells prevented colitis (reduced colitis scores, mucosal hypertrophy, TNF, and intestinal permeability). PCR array analyses demonstrated the influence of mast cells on cytokine expression. Analysis of the microbiota revealed sex-specific differences between IL10 and DKO mice, in particular, the abundance of Akkermansia muciniphila, a mucus degrader associated with colitis. Derivation of DKO mice into a germ-free environment revealed that the microbiota is required for disease development. RNA-seq on colon samples revealed candidate genes for the protective effects of mast cells. These results demonstrate that mast cell deficiency exacerbates disease in a chronic, spontaneous IBD model, indicating that mast cells may have protective functions in IBD, and potentially other chronic inflammatory disorders.