IL-17A-Mediated Regulation of Stromal and Epithelial Cell Interactions in the Intestine

About This Grant

Abstract The IL-17 family of cytokines is extensively studied and plays a crucial role in immunity and inflammation. While anti-IL-17A or anti-IL-17RA therapies are commonly used to treat patients with plaque psoriasis, they have been unsuccessful in treating inflammatory bowel disease (IBD) and, in some cases, have even worsened the condition. There have also been reports of new-onset IBD in individuals receiving IL-17A-neutralizing therapies. Additionally, the colonic epithelium of IBD patients often accumulates mutations that affect IL-17A signaling. These findings, counterintuitively, suggest that IL-17A responses in the gut may be beneficial. Published studies have shown that IL-17A responses in intestinal epithelial cells are critical for maintaining gut barrier integrity, supporting intestinal Th17 immune responses, regulating epithelial redox balance (via Nox1-H₂O₂), and controlling colonization by segmented filamentous bacteria (SFB). However, there remains a significant gap in understanding of the molecular mechanisms through which IL-17A promotes mucosal host defense. In addition to the epithelium and Lgr5+ intestinal stem cells (ISCs), certain intestinal mesenchymal stromal cell subsets— such as telocytes and trophocytes—also express the IL-17A receptor complex (IL-17RA/IL-17RC). At present, little is known about the role of IL-17A in these stromal subsets. Preliminary studies have identified a previously unreported function of IL-17A in activating stromal cells to induce a fetal-like reprogramming of epithelial cells. The central hypothesis of this proposal is that IL-17RA signaling in stromal cells is essential for epithelial regeneration. Aim 1 will define IL-17A-dependent regulatory pathways in specific intestinal stromal cell subsets. Aim 2 will investigate how stromal cell function supports epithelial regeneration. Aim 3 will explore stromal cell induced epithelial regeneration pathway in IBD. Impaired intestinal epithelial regeneration is a hallmark of IBD. The successful completion of these studies will have broad implications for a range of diseases, both within and beyond the gut, in which tissue regeneration is compromised.