IL-22 promotes mucin-type O-glycosylation and MATH1+ cell-mediated amelioration of intestinal inflammation

The interleukin (IL)-22 cytokine can be protective or inflammatory in the intestine. It is unclear if IL-22 receptor (IL-22Ra1)-mediated protection involves a specific type of intestinal epithelial cell (IEC). By using a range of IEC type-specific Il22Ra1 conditional knockout mice and a dextran sulfate sodium (DSS) colitis model, we demonstrate that IL-22Ra1 signaling in MATH1+ cells (goblet and progenitor cells) is essential for maintaining the mucosal barrier and intestinal tissue regeneration. The IL-22Ra1 signaling in IECs promotes mucin core-2 O-glycan extension and induces beta-1,3-galactosyltransferase 5 (B3GALT5) expression in the colon. Adenovirus-mediated expression of B3galt5 is sufficient to rescue Il22Ra1IEC mice from DSS colitis. Additionally, we observe a reduction in the expression of B3GALT5 and the Tn antigen, which indicates defective mucin O-glycan, in the colon tissue of patients with ulcerative colitis. Lastly, IL-22Ra1 signaling in MATH1+ progenitor cells promotes organoid regeneration after DSS injury. Our findings suggest that IL-22-dependent protective responses involve O-glycan modification, proliferation, and differentiation in MATH1+ progenitor cells. [Display omitted] •IL-22Ra1-B3GALT5 axis in intestinal epithelium protects from colitis development•IL-22Ra1-B3GALT5 axis is involved in altering O-glycan profile of mucin•IL-22Ra1 signaling in MATH1+ cells provides protection from colitis development•IL-22Ra1 signaling in MATH1+ progenitor regenerates epithelium post-DSS treatment Singh et al.’s study shows that the IL-22Ra1-B3GALT5 axis is important in intestinal epithelial cells to protect from DSS colitis. The intestinal epithelial target of IL-22 is MATH1+ cells, which regulate B3galt5 expression (mainly goblet cells) and induce epithelial regeneration (MATH1+ progenitor cells) to protect from the development of DSS colitis.