Intestinal IL-17RA signaling and mucosal host defense

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Inflammatory bowel disease (IBD), which comprises Ulcerative Colitis (UC) and Crohn’s Disease (CD), is a devastating disease that impacts millions of people in the United States. The underlying mechanisms leading to IBD are poorly understood. Paneth cells and their antimicrobial products (a-defensins, lysozyme etc.) play a critical role in small intestinal host defense and their dysregulation constitutes a pathogenic factor for CD. CD patients have Paneth cell abnormalities, reduced expression of a-defensins and elevated levels of IL-17A in the inflamed tissue. The IL-17A/IL-17F axis is a known driver of intestinal inflammatory and protective responses in mouse models and human IBD, but little is known regarding the specific cellular niches of IL- 17A/F receptor signaling and the molecular mechanisms of IL-17A-mediated host defense in the intestines. We were the first to show that the abrogation of intestinal IL-17A host defense responses leads to commensal dysbiosis and dysregulated immune responses in the small intestine. Despite the myriad of gastrointestinal tract responses to IL-17A stimulation, the literature has failed to elucidate whether the defense responses to injury or infection are a result of direct stimulation to functionally distinct absorptive or secretory mature epithelial cell types or if they are stem cell-derived consequences. Therefore, it is not known whether IL-17A directly or indirectly modulates Paneth and other cell types effector function in the gut. We found that IL-17A/F receptor (IL-17RA/IL-17RC) is expressed on functionally distinct absorptive cells (enterocytes), secretory cells (Paneth), Lgr5+ intestinal stem cells (ISCs) and transit-amplifying (TA) progenitor cells of the intestine. However, almost nothing is known regarding whether IL-17A directly or indirectly modulates Paneth cells, ISCs and progenitor cells function. We now have compelling evidence suggesting that IL-17A directly regulates unique and specific functions in Paneth cells, ISCs and ATOH1+ progenitor cells of intestine. ATOH1 is required for lineage commitment of intestinal secretory cells, including Paneth cells. To investigate lineage- specific function, we generated and validated entire gut epithelium (Villin-cre), Paneth cell (Defa6-cre) and Atoh1-specific (Atoh1-cre) novel IL-17RA (Il17rafl/fl) conditional knockout mice. The proposed studies in Aim 1 will seek to understand the role of IL-17RA signaling in regulating ISC and Paneth cell function under homeostatic conditions. In Aim 2, using multiple models of intestinal inflammation and our lineage-specific IL- 17RA conditional knockout mice, we will determine how IL-17A regulates unique and novel functions in specific cell types in the small and large intestine, respectively. These studies will have a direct impact in IBD research to understand the novel role of IL-17RA signaling major cell types of the small and large intestine. Completion of these studies will provide a needed understanding of the complex molecular mechanisms of actions of IL- 17A in regulating intestinal inflammation.