Abrogation of IL-13Rα2 ameliorates acute inflammatory bowel disease

Abstract

Abstract Anti-TNFα agents are commonly used for treatment of patients with inflammatory bowel disease (IBD), yet up to 40% of patients are non-responders for unknown reasons. IL13RA2 mRNA was more abundant in mucosal biopsy samples of patients with active IBD who are non-responders compared to responders, serving as a potential predictive marker for non-responsiveness. IL-13Rα2 is a high affinity decoy receptor for IL-13, a cytokine with both anti-inflammatory and wound healing functions. In this study, we hypothesized that TNFα and IL-17 produced during the initiation of IBD induces IL-13Rα2 production that neutralizes the endogenous anti-inflammatory activity of IL-13. Using an acute dextran sodium sulfate (DSS) model of mouse colitis, we show that DSS increases the production of both systemic and colonic IL-13Rα2 compared to naive controls. DSS-induced colitis was less severe in Il13ra2−/− mice compared to wild type controls as no shortening in the length of the colon was observed. Histological analysis of the distal colon revealed less goblet cell depletion, inflammatory cell infiltration, and submucosal inflammation in DSS-administered Il13ra2−/− mice compared to DSS-administered wild type mice. However, when Il13ra2−/− mice were infected with the nematode Heligmosomoides polygyrus bakeri, the increased IL-13 activity led to significant morbidity during DSS-colitis. Together, these findings suggest that the absence of IL-13Rα2 enhances endogenous IL-13 bioactivity, which protects mice from acute IBD. Yet, results from the nematode infection model suggest this protective activity must be carefully regulated. Collectively, these results suggest that IL-13Rα2 functions as a key regulator of IBD pathogenesis.