Control of inflammation by stromal Hedgehog pathway activation restrains colitis

Significance Inflammatory bowel disease (IBD) is a debilitating disorder with limited treatment options. Here, we report that manipulation of Hedgehog (Hh) pathway signaling affects disease severity in the well-established dextran sulfate mouse model of colitis. Genetic and pharmacologic manipulations that decrease Hh pathway signaling in the colon worsen colitis. Conversely, manipulations that increase Hh pathway signaling ameliorate colitis. We find that Hh pathway stimulation exerts its effects partially through increased expression of the antiinflammatory cytokine IL-10 in Hh pathway-responsive stromal cells and concomitant increases in CD4 + Foxp3 + regulatory T cells in the colon. Our studies suggest that pharmacologic Hh pathway stimulation in colonic stromal cells may be a strategy to treat IBD.