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

doi:10.1038/s41467-023-40993-5

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

Health Sciences Administration

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2 Scopus citations

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 language	English (US)
Article number	5411
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-40993-5
State	Published - Dec 2023

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© 2023, Springer Nature Limited.

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Calafiore, M., Fu, Y. Y., Vinci, P., Arnhold, V., Chang, W. Y., Jansen, S. A., Egorova, A., Takashima, S., Kuttiyara, J., Ito, T., Serody, J., Nakae, S., Turnquist, H., van Es, J., Clevers, H., Lindemans, C. A., Blazar, B. R., & Hanash, A. M. (2023). A tissue-intrinsic IL-33/EGF circuit promotes epithelial regeneration after intestinal injury. Nature communications, 14(1), Article 5411. https://doi.org/10.1038/s41467-023-40993-5

Calafiore, M, Fu, YY, Vinci, P, Arnhold, V, Chang, WY, Jansen, SA, Egorova, A, Takashima, S, Kuttiyara, J, Ito, T, Serody, J, Nakae, S, Turnquist, H, van Es, J, Clevers, H, Lindemans, CA, Blazar, BR & Hanash, AM 2023, 'A tissue-intrinsic IL-33/EGF circuit promotes epithelial regeneration after intestinal injury', Nature communications, vol. 14, no. 1, 5411. https://doi.org/10.1038/s41467-023-40993-5

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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.",

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

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AU - Serody, Jonathan

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AU - Turnquist, Heth

AU - van Es, Johan

AU - Clevers, Hans

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AU - Blazar, Bruce R.

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N2 - 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.

AB - 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.

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

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