A tissue-intrinsic IL-33/EGF circuit promotes epithelial regeneration after intestinal injury

Marco Calafiore, Ya Yuan Fu, Paola Vinci, Viktor Arnhold, Winston Y. Chang, Suze A. Jansen, Anastasiya Egorova, Shuichiro Takashima, Jason Kuttiyara, Takahiro Ito, Jonathan Serody, Susumu Nakae, Heth Turnquist, Johan van Es, Hans Clevers, Caroline A. Lindemans, Bruce R. Blazar, Alan M. Hanash*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Intestinal stem cells (ISCs) maintain the epithelial lining of the intestines, but mechanisms regulating ISCs and their niche after damage remain poorly understood. Utilizing radiation injury to model intestinal pathology, we report here that the Interleukin-33 (IL-33)/ST2 axis, an immunomodulatory pathway monitored clinically as an intestinal injury biomarker, regulates intrinsic epithelial regeneration by inducing production of epidermal growth factor (EGF). Three-dimensional imaging and lineage-specific RiboTag induction within the stem cell compartment indicated that ISCs expressed IL-33 in response to radiation injury. Neighboring Paneth cells responded to IL-33 by augmenting production of EGF, which promoted ISC recovery and epithelial regeneration. These findings reveal an unknown pathway of niche regulation and crypt regeneration whereby the niche responds dynamically upon injury and the stem cells orchestrate regeneration by regulating their niche. This regenerative circuit also highlights the breadth of IL-33 activity beyond immunomodulation and the therapeutic potential of EGF administration for treatment of intestinal injury.

Original languageEnglish
Article number5411
Pages (from-to)1-13
Number of pages13
JournalNature Communications
Volume14
Issue number1
DOIs
Publication statusPublished - 5 Sept 2023

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