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

  • Sci China Life Sci. 2025 Oct 14. doi: 10.1007/s11427-024-2923-2.
Qihang Hou  #  1  2 ,  Yong Zhang  #  3 ,  Lihua Zhao  #  1 ,  Yujiao Lai  1 ,  Junyou Li  4 ,  Yunshan Zhao  5 ,  Yang Yang  5 ,  Xin Yang  2 ,  Xiaojun Yang  2 ,  Bingkun Zhang  6
Affiliations
  • 1. State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science & Technology, China Agricultural University, Beijing, 100193, China.
  • 2. College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China.
  • 3. Senior Department of General Surgery, the First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China.
  • 4. Graduate School of Agricultural and Life Sciences, The University of Tokyo, Ibaraki, 319-0206, Japan.
  • 5. DarkJade Sciences, Inc., Beijing, 100192, China.
  • 6. State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science & Technology, China Agricultural University, Beijing, 100193, China. [email protected].
  • # Contributed equally.
PMID: 41107660 DOI: 10.1007/s11427-024-2923-2
Abstract

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.

Keywords
5-FU; IL-15/IL-15Rα; intestinal stromal cell; organoid; regeneration.
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