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

Paneth cells are critical defenders of the small intestine, supporting antimicrobial protection and contributing to epithelial maintenance. Recent evidence shows that they can adopt stem-like properties to regenerate damaged crypts after injury. However, the signals that enable this regenerative shift are not well understood. This project investigates the role of IL-17A signaling through its receptor, IL-17RA, in driving Paneth cell mediated epithelial repair. Using Paneth cell specific IL-17RA knockout mice, IL-17A neutralization, and lineage tracing models, we find that IL-17RA signaling is required for Paneth cells to acquire stem-like features and regenerate the epithelium following injury. Loss of IL-17RA increases injury susceptibility and reduces expression of Adam17 in the terminal ileum, while restoring Adam17 rescues the regeneration defect, demonstrating a functional link between IL-17RA signaling and ADAM17 dependent repair. Mechanistic studies show that IL-17A induces Nox1 in Paneth cells, H2O2 enhances ADAM17 enzymatic activity, and Paneth cell specific Adam17 knockout confirms that ADAM17 is required for tissue regeneration. Together, these findings establish an IL-17RA-Nox1-ADAM17 pathway as a key driver of Paneth cell mediated regeneration. The goals of this work are to determine whether IL-17RA signaling enables Paneth cells to gain stem-like properties, define the pathway linking IL-17A and IL-17RA to ADAM17 activation, and establish the requirement of ADAM17 in crypt regeneration. This research is highly relevant to conditions marked by epithelial injury, including inflammatory bowel disease, and irradiation therapy induced mucosal damage. This research may inform strategies to enhance mucosal healing and preserve intestinal integrity when regenerative capacity is impaired.