Role of IL-33 in murine models of intestinal inflammation. Experimental results obtained from SAMP mice that develop spontaneous Th1/Th2-driven enteritis suggest a pathogenic role for IL-33 at the onset of intestinal inflammation in this specific model. In fact, epithelial-derived IL-33 promotes the release of proinflammatory cytokines from LP immune cells, enhancing both Th1 and Th2 responses. Moreover, IL-33 induces the production of eotaxin-1 and eotaxin-2, which leads to eosinophil chemotaxis to the inflamed gut. In addition, IL-33 activates the expression of profibrotic genes, contributing to the development of intestinal fibrosis (upper panel). Different results are observed in chemically induced models of intestinal inflammation (middle and lower panels). During the onset of acute DSS-induced colitis, IL-33, likely released by necrotic/damaged epithelial cells, participates in the development of intestinal inflammation with a potent chemotactic effect on neutrophils, cells that play a pivotal role in this specific model of colitis (middle panel). Conversely, during the recovery phase of chronic DSS colitis, IL-33 appears to promote wound healing, inducing the restoration of epithelial barrier integrity. On the contrary, when IL-33 is administered to mice displaying a TNBS-induced colitis, which is mainly driven by a Th1 immune response, IL-33 shows an anti-inflammatory effect as a result of the skewing towards a Th2 immunophenotype and the potential induction of T regulatory cell activation (lower panel).
