2. Academic Validation
  3. Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair

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

  • Cell. 2024 Nov 4:S0092-8674(24)01158-9. doi: 10.1016/j.cell.2024.10.010.
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

Affiliations

  • 1 Division of Immunology, Harvard Medical School and Boston Children's Hospital, Boston, MA 02115, USA.
  • 2 Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), 13288 Marseille Cedex, France.
  • 3 Division of Immunology, Harvard Medical School and Boston Children's Hospital, Boston, MA 02115, USA; Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany.
  • 4 Division of Gastroenterology, Harvard Medical School and Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
  • 5 Department of Immunology, Tufts University School of Medicine, Boston, MA 02111, USA.
  • 6 Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA, USA.
  • 7 Division of Gastroenterology, Harvard Medical School and Boston Children's Hospital, Boston, MA 02115, USA.
  • 8 Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
  • 9 Department of Integrative Biology and Physiology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
  • 10 State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 210061, China.
  • 11 Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Center for Molecular inflammation Research, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway.
  • 12 National Institute of Biological Sciences, Beijing 102206, China.
  • 13 Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), 13288 Marseille Cedex, France. Electronic address: broggi@ciml.univ-mrs.fr.
  • 14 Division of Immunology, Harvard Medical School and Boston Children's Hospital, Boston, MA 02115, USA; Division of Gastroenterology, Harvard Medical School and Boston Children's Hospital, Boston, MA 02115, USA; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ivan.zanoni@childrens.harvard.edu.
PMID: 39500322 DOI: 10.1016/j.cell.2024.10.010
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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