Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability

Whether interleukin-17A (IL-17A) has pathogenic and/or protective roles in the gut mucosa is controversial and few studies have analyzed specific cell populations for protective functions within the inflamed colonic tissue. Here we have provided evidence for IL-17A-dependent regulation of the tight junction protein occludin during epithelial injury that limits excessive permeability and maintains barrier integrity. Analysis of epithelial cells showed that in the absence of signaling via the IL-17 receptor adaptor protein Act-1, the protective effect of IL-17A was abrogated and inflammation was enhanced. We have demonstrated that after acute intestinal injury, IL-23R+ γδ T cells in the colonic lamina propria were the primary producers of early, gut-protective IL-17A, and this production of IL-17A was IL-23 independent, leaving protective IL-17 intact in the absence of IL-23. These results suggest that IL-17-producing γδ T cells are important for the maintenance and protection of epithelial barriers in the intestinal mucosa. •Neutralizing IL-17 results in increased gut permeability in a DSS injury model•γδ T cells are the major source of gut-protective IL-17 and are IL-23 independent•IL-17 regulates the cellular localization of the tight junction protein occludin•The data explain IBD exacerbation with anti-IL-17 but amelioration with anti-IL-23 Neutralizing IL-17 has efficacy in psoriasis but is ineffective for the treatment of Crohn’s disease. Cua and colleagues demonstrate that IL-23-independent γδ T cell-derived IL-17 regulates occludin tight junction protein and limits gut permeability. Anti-IL-23 therapy preserves protective IL-17 while limiting inflammation during acute gut injury.