IL-22-deficiency mediates resolution of colitis in Il10 −/− mice

Abstract The cytokines IL-10 and IL-22 play important, but presumably distinct roles in promoting intestinal homeostasis. Although the anti-inflammatory actions of IL-10 in the gut are well established, the role(s) of IL-22 remain unclear. Il10−/− mice develop chronic colitis characterized by rectal prolapse, colonic thickening and inflammatory infiltrates, including abundant Th17 cells. We have also observed a modest, but consistent elevation in IL-22 (mRNA and IL-22+CD4 T cells) in colons of Il10−/− mice. This is accompanied by an increased expression of IL-22-target bactericidal genes such as Reg3g, s100a8, and s100a9 and reduced intestinal microbial diversity in Il10−/− mice. To define a potential role for IL-22 in spontaneous colitis, we generated Il10−/− Il22−/− mice by backcrossing. Unexpectedly, concurrent IL-22 deficiency prevented colitis in Il10−/− mice, normalizing histopathology inflammatory scores and restoring microbial diversity to WT levels in Il10−/− Il22−/− mice, despite endemic Helicobacter spp. infection, an established risk factor for colitis in Il10−/− mice. Interestingly, prevention of disease was not accompanied by a reduction in Th17 cells. Importantly, introduction of recombinant IL-22 into the GI tracts of both Il10−/− Il22−/− and WT mice resulted in colonic shortening and thickening after only 2 weeks of treatment, suggesting that IL-22 is at least partially responsible for the immunopathology observed in Il10−/− mice. Thus, although beneficial during certain bacterial infections and in response to acute tissue damage, our data suggest that left unchecked, IL-22 expression can contribute to chronic colitis and appears to be negatively regulated by IL-10.