The development of colitis in Il10(−/−) mice is dependent on IL-22

Mice deficient in the IL-10 pathway are the most widely-used models of intestinal immunopathology.IL-17A is strongly implicated in gut disease in mice and humans, but conflicting evidence has drawn IL-17’s role in the gut into question.IL-22 regulates antimicrobial and repair activities of intestinal epithelial cells (IECs) and is closely associated with IL-17A responses but it’s role in chronic disease is uncertain. We report that IL-22, like IL-17A, is aberrantly expressed in colitic Il10(−/−) mice. While IL-22(+)Th17 cells were elevated in the colon, IL-22-producing ILC3s were highly enriched in the small intestines of Il10(−/−) mice. Remarkably, Il10(−/−)Il22(−/−) mice did not develop colitis despite retaining high levels of Th17 cells and remaining colonized with colitogenic Helicobacter spp.. Accordant with IL-22-induced IEC proliferation, the epithelia hyperplasia observed in Il10(−/−) animals was reversed in Il10(−/−)Il22(−/−) mice. Also, the high levels of antimicrobial IL-22-target genes, including Reg3g, were normalized in Il10(−/−)Il22(−/−) mice. Consistent with a heightened antimicrobial environment, Il10(−/−) mice had reduced diversity of the fecal microbiome that was reestablished in Il10(−/−)Il22(−/−) animals. These data suggest that spontaneous colitis in Il10(−/−) mice is driven by IL-22 and implicates an underappreciated IL-10-IL-22 axis in regulating intestinal homeostasis.