PT  - JOURNAL ARTICLE
AU  - Benedetta Sposito
AU  - Julien Mambu
AU  - Katlynn Bugda Gwilt
AU  - Lionel Spinelli
AU  - Natalia Andreeva
AU  - Franck Galland
AU  - Philippe Naquet
AU  - Vanessa Mitsialis
AU  - Jay R Thiagarajah
AU  - Scott B Snapper
AU  - Achille Broggi
AU  - Ivan Zanoni
TI  - Type III interferons induce pyroptosis in gut epithelial cells and delay tissue restitution upon acute intestinal injury
AID  - 10.1101/2022.03.04.482997
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.03.04.482997
4099  - http://biorxiv.org/content/early/2022/03/04/2022.03.04.482997.short
4100  - http://biorxiv.org/content/early/2022/03/04/2022.03.04.482997.full
AB  - Tissue damage and repair are hallmarks of the inflammatory process. Despite a wealth of information focused on the mechanisms that govern tissue damage, mechanistic insight on how inflammatory immune mediators affect the restitution phase is lacking. Here, we investigated how interferons influence tissue restitution after damage of the intestinal mucosa driven by inflammatory or physical injury. We found that type III, but not type I, interferons serve a central role in the restitution process. Type III interferons induce the upregulation of ZBP1, caspase activation, and cleavage of gasdermin C, and drive epithelial cell death by pyroptosis, thus delaying tissue restitution. We also found that this pathway is transcriptionally regulated in IBD patients. Our findings highlight a new molecular signaling cascade initiated by the immune system that affects the outcome of the immune response by delaying tissue repair and that may have important implications for human inflammatory disorders.Competing Interest StatementThe authors have declared no competing interest.