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 and Alan M. Hanash ()
Additional contact information
Marco Calafiore: Memorial Sloan Kettering Cancer Center
Ya-Yuan Fu: Memorial Sloan Kettering Cancer Center
Paola Vinci: Memorial Sloan Kettering Cancer Center
Viktor Arnhold: Memorial Sloan Kettering Cancer Center
Winston Y. Chang: Memorial Sloan Kettering Cancer Center
Suze A. Jansen: University Medical Center Utrecht, Utrecht University
Anastasiya Egorova: Memorial Sloan Kettering Cancer Center
Shuichiro Takashima: Memorial Sloan Kettering Cancer Center
Jason Kuttiyara: Memorial Sloan Kettering Cancer Center
Takahiro Ito: Memorial Sloan Kettering Cancer Center
Jonathan Serody: University of North Carolina
Susumu Nakae: Hiroshima University, Higashi-Hiroshima City
Heth Turnquist: University of Pittsburgh School of Medicine
Johan van Es: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW)
Hans Clevers: Princess Máxima Center for Pediatric Oncology
Caroline A. Lindemans: University Medical Center Utrecht, Utrecht University
Bruce R. Blazar: University of Minnesota
Alan M. Hanash: Memorial Sloan Kettering Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40993-5

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