Stroma-specific IL-15 coordinates epithelial IL-15Rα to promote intestinal epithelial repair

Interleukin (IL)-15 is critical for intestinal homeostasis, but the precise origin and functions of IL-15 involved in inflamed mucosal healing are not fully understood. This study demonstrated that IL-15/IL-15Rα signaling was up-regulated during wound healing in 5-fluorouracil (5-FU)-induced intestinal mucositis. Moreover, a subset of podoplanin⁺ stromal cells located adjacent to crypts were the primary cellular source of IL-15 following gut damage. Stroma-specific IL-15 proved to be crucial for the regeneration of damaged intestine. The deletion of IL-15Rα in intestinal epithelial cells compromised the recovery from intestinal injury. Moreover, compared with IL-15, IL-15/IL-15Rα complex can more efficiently promote intestinal epithelial repair. When stimulating human-derived ileal organoids, IL-15/IL-15 complex induced epithelial proliferation through an STAT3-HIF-1α signaling axis and afforded protection against 5-FU-induced epithelial damage. These findings innovatively demonstrated that stroma-specific IL-15 coordinates epithelial IL-15Rα to accelerate wound healing in response to gut damage.