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. 2024 Dec 26;187(26):7533-7550.e23.
doi: 10.1016/j.cell.2024.10.010. Epub 2024 Nov 4.

Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair

Kautilya K Jena  1 , Julien Mambu  2 , Daniel Boehmer  3 , Benedetta Sposito  1 , Virginie Millet  2 , Joshua de Sousa Casal  4 , Hayley I Muendlein  5 , Roberto Spreafico  6 , Romain Fenouil  2 , Lionel Spinelli  2 , Sarah Wurbel  2 , Chloé Riquier  2 , Franck Galland  2 , Philippe Naquet  2 , Lionel Chasson  2 , Megan Elkins  1 , Vanessa Mitsialis  7 , Natália Ketelut-Carneiro  8 , Katlynn Bugda Gwilt  7 , Jay R Thiagarajah  7 , Hai-Bin Ruan  9 , Zhaoyu Lin  10 , Egil Lien  11 , Feng Shao  12 , Janet Chou  1 , Alexander Poltorak  5 , Jose Ordovas-Montanes  4 , Katherine A Fitzgerald  8 , Scott B Snapper  7 , Achille Broggi  13 , Ivan Zanoni  14
Affiliations

Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair

Kautilya K Jena et al. Cell. .

Abstract

Tissue damage and repair are hallmarks of inflammation. Despite a wealth of information on the mechanisms that govern tissue damage, mechanistic insight into how inflammation affects repair is lacking. Here, we investigated how interferons influence tissue repair after damage to the intestinal mucosa. We found that type III, not type I or type II, interferons delay epithelial cell regeneration by inducing the upregulation of Z-DNA-binding protein 1 (ZBP1). Z-nucleic acids formed following intestinal damage are sensed by ZBP1, leading to caspase-8 activation and the cleavage of gasdermin C (GSDMC). Cleaved GSDMC drives epithelial cell death by pyroptosis and delays repair of the large or small intestine after colitis or irradiation, respectively. The type III interferon/ZBP1/caspase-8/GSDMC axis is also active in patients with inflammatory bowel disease (IBD). Our findings highlight the capacity of type III interferons to delay gut repair, which has implications for IBD patients or individuals exposed to radiation therapies.

Keywords: Z-nucleic acid; colitis; damage; gasdermin; inflammation; inflammatory bowel disease; interferons; intestinal epithelial cell; intestinal stem cell; irradiation; pattern recognition receptors; pyroptosis; repair.

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Conflict of interest statement

Declaration of interests I.Z., A.B., and S.B.S. have submitted a patent related to the matter of this paper.

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