IL-17RA signaling promotes the dedifferentiation of Paneth progenitors through ADAM17 to regenerate gut epithelium post-irradiation

Paneth cells and their antimicrobial products are critical in mediating small intestinal host defense under homeostatic conditions and after injury or infection. In addition, Paneth cells have also been shown to gain stem-like properties and repropagate intestinal crypts after intestinal injury. The specific role of intestinal IL-17A or its receptor (IL-17RA) signaling in Paneth cells to gain stem-like features has yet to be investigated. Using Paneth cell-specific IL-17RA (Il17ra^fl/fl;Defa6-cre) knockout mice, anti-IL-17A neutralizing studies and lineage tracer (Defa6-cre;mT/mG) mice, we show that after injury IL-17RA signaling is required for Paneth cell to gain stem-like properties to regenerate the intestinal epithelium. Increased susceptibility of Il17ra^fl/fl;Defa6-cre mice is associated with reduced expression Adam17 in the terminal ileum. Adam17 overexpression in Il17ra^fl/fl;Defa6-cre mice rescues the epithelial regeneration defect in these mice. IL-17A induces Nox1 in Paneth cells and H₂O₂ induces ADAM17 enzymatic activity. Finally, using Paneth cell-specific Adam17 (Adam17^fl/fl;Defa6-cre) knockout mice, we show that ADAM17 in Paneth cells is required for tissue regeneration. Collectively, our data reveal an essential role of the IL-17RA-ADAM17 pathways in Paneth cells for tissue regeneration.