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The Regulation of Interleukin-13 by IL-13Rα2 Determines the Severity of Murine Inflammatory Bowel Disease Open Access

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The balance between pro-inflammatory and anti-inflammatory cytokine responses is a major determinant of disease progression in both Crohn’s disease (CD) and ulcerative colitis (UC). CD and UC are inflammatory bowel diseases (IBD) usually characterized by periods of exacerbation and remission. Although the cytokine IL-13 serves as a key mediator of type 2 cytokine-dependent allergic inflammation, it can play a protective role in IBD and other type 1- and 17-associated diseases by cross-regulating IFN-gamma and IL-17 responses. IL-13Rα2 is a decoy receptor that binds IL-13 with high affinity and diminishes its STAT6-mediated effector functions. Previously, we found that IL-13Rα2 was required for piroxicam- and Trichuris muris-induced colitis in mice deficient in the anti-inflammatory cytokine IL-10. Here, we tested for the first time a therapeutic antibody specifically targeting IL-13Rα2. We also used Il13ra2–/– mice to dissect the role of IL-13Rα2 in IBD pathogenesis and recovery using the dextran sodium sulfate (DSS) model of colitis. Following a seven-day recovery period from DSS-induced colitis, Il13ra2–/– mice or wild type mice administered the IL-13Rα2-neutralizing antibody had significantly improved colon health compared to control mice. However, we also uncovered an unexpected protective role for IL-13Rα2 in the pathogenesis of IBD in mice with elevated IL-13 present during the induction of colitis. Together these studies reveal dual roles for IL-13Rα2 in IBD pathogenesis, with IL-13Rα2 reducing susceptibility to DSS-induced IBD while playing a detrimental role during the recovery phase by limiting the pro-regenerative and type 1-inhibitory activities of IL-13. Thus, IL-13Rα2 functions as a rheostat of intestinal health by tightly controlling critical IL-13 effector functions during the initiation and resolution phases of IBD.

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