Dichotomous consequences of IL-23 signaling in chemically induced colitis in mice (59.2)

Abstract The interleukin-23 (IL-23) pathway has emerged as a promising therapeutic target for inflammatory bowel disease and blockade of IL-23 signaling is beneficial in mouse models of intestinal inflammation. Although the pathogenic role of IL-23R on T lymphocytes is well established, the function of IL-23R on innate immune cells has not been thoroughly examined. Here we investigate the consequence of IL-23R deletion in dextran sodium sulfate (DSS)-induced colitis, a chemically-induced acute model of inflammatory bowel disease. In IL23R-/- and IL23p19-/- mice, we observed decreased weight loss, improved histological scores, and reduced leukocyte infiltrate following DSS exposure. Surprisingly, when the IL-23R-/- allele was crossed into Rag2-/- mice, we observed exacerbated disease characterized by delayed recovery, increased epithelial damage, and reduced pSTAT3 in the epithelium in IL23R-/-Rag2-/- mice. This defect in epithelial repair in IL23R-/-Rag2-/- mice was rescued with exogenous IL22-Fc, and epithelial pSTAT3 was restored to normal levels. Depletion of Thy1+ innate lymphoid cells eliminated the majority of IL22 production in the colon lamina propria of DSS-treated mice, suggesting that these are the major IL-23 responsive innate cells in this context. In summary, we provide evidence for a protective role of IL-23 in murine colitis with implications in the therapeutic blockade of IL-23 signaling.