The development of colitis in Il10-/- mice is dependent on IL-22.

ABSTRACT

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.