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

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

doi:10.1016/j.cell.2024.10.010

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

Kautilya K. Jena, Julien Mambu, Daniel Boehmer, Benedetta Sposito, Virginie Millet, Joshua de Sousa Casal, Hayley I. Muendlein, Roberto Spreafico, Romain Fenouil, Lionel Spinelli, Sarah Wurbel, Chloé Riquier, Franck Galland, Philippe Naquet, Lionel Chasson, Megan Elkins, Vanessa Mitsialis, Natália Ketelut-Carneiro, Katlynn Bugda Gwilt, Jay R. ThiagarajahHai Bin Ruan, Zhaoyu Lin, Egil Lien, Feng Shao, Janet Chou, Alexander Poltorak, Jose Ordovas-Montanes, Katherine A. Fitzgerald, Scott B. Snapper, Achille Broggi, Ivan Zanoni

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English
Pages (from-to)	7533-7550.e23
Journal	Cell
Volume	187
Issue number	26
DOIs	https://doi.org/10.1016/j.cell.2024.10.010
State	Published - 26 Dec 2024
Externally published	Yes

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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10.1016/j.cell.2024.10.010

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Jena, K. K., Mambu, J., Boehmer, D., Sposito, B., Millet, V., de Sousa Casal, J., Muendlein, H. I., Spreafico, R., Fenouil, R., Spinelli, L., Wurbel, S., Riquier, C., Galland, F., Naquet, P., Chasson, L., Elkins, M., Mitsialis, V., Ketelut-Carneiro, N., Bugda Gwilt, K., ... Zanoni, I. (2024). Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair. Cell, 187(26), 7533-7550.e23. https://doi.org/10.1016/j.cell.2024.10.010

@article{92f555e79bbb4f68aabb19009da34b64,

title = "Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair",

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",

author = "Jena, {Kautilya K.} and Julien Mambu and Daniel Boehmer and Benedetta Sposito and Virginie Millet and {de Sousa Casal}, Joshua and Muendlein, {Hayley I.} and Roberto Spreafico and Romain Fenouil and Lionel Spinelli and Sarah Wurbel and Chlo{\'e} Riquier and Franck Galland and Philippe Naquet and Lionel Chasson and Megan Elkins and Vanessa Mitsialis and Nat{\'a}lia Ketelut-Carneiro and {Bugda Gwilt}, Katlynn and Thiagarajah, {Jay R.} and Ruan, {Hai Bin} and Zhaoyu Lin and Egil Lien and Feng Shao and Janet Chou and Alexander Poltorak and Jose Ordovas-Montanes and Fitzgerald, {Katherine A.} and Snapper, {Scott B.} and Achille Broggi and Ivan Zanoni",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Inc.",

year = "2024",

month = dec,

day = "26",

doi = "10.1016/j.cell.2024.10.010",

language = "English",

volume = "187",

pages = "7533--7550.e23",

journal = "Cell",

issn = "0092-8674",

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Jena, KK, Mambu, J, Boehmer, D, Sposito, B, Millet, V, de Sousa Casal, J, Muendlein, HI, Spreafico, R, Fenouil, R, Spinelli, L, Wurbel, S, Riquier, C, Galland, F, Naquet, P, Chasson, L, Elkins, M, Mitsialis, V, Ketelut-Carneiro, N, Bugda Gwilt, K, Thiagarajah, JR, Ruan, HB, Lin, Z, Lien, E, Shao, F, Chou, J, Poltorak, A, Ordovas-Montanes, J, Fitzgerald, KA, Snapper, SB, Broggi, A & Zanoni, I 2024, 'Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair', Cell, vol. 187, no. 26, pp. 7533-7550.e23. https://doi.org/10.1016/j.cell.2024.10.010

TY - JOUR

T1 - Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair

AU - Jena, Kautilya K.

AU - Mambu, Julien

AU - Boehmer, Daniel

AU - Sposito, Benedetta

AU - Millet, Virginie

AU - de Sousa Casal, Joshua

AU - Muendlein, Hayley I.

AU - Spreafico, Roberto

AU - Fenouil, Romain

AU - Spinelli, Lionel

AU - Wurbel, Sarah

AU - Riquier, Chloé

AU - Galland, Franck

AU - Naquet, Philippe

AU - Chasson, Lionel

AU - Elkins, Megan

AU - Mitsialis, Vanessa

AU - Ketelut-Carneiro, Natália

AU - Bugda Gwilt, Katlynn

AU - Thiagarajah, Jay R.

AU - Ruan, Hai Bin

AU - Lin, Zhaoyu

AU - Lien, Egil

AU - Shao, Feng

AU - Chou, Janet

AU - Poltorak, Alexander

AU - Ordovas-Montanes, Jose

AU - Fitzgerald, Katherine A.

AU - Snapper, Scott B.

AU - Broggi, Achille

AU - Zanoni, Ivan

PY - 2024/12/26

Y1 - 2024/12/26

N2 - 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.

AB - 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.

KW - Z-nucleic acid

KW - colitis

KW - damage

KW - gasdermin

KW - inflammation

KW - inflammatory bowel disease

KW - interferons

KW - intestinal epithelial cell

KW - intestinal stem cell

KW - irradiation

KW - pattern recognition receptors

KW - pyroptosis

KW - repair

UR - http://www.scopus.com/inward/record.url?scp=85210103835&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2024.10.010

DO - 10.1016/j.cell.2024.10.010

M3 - Article

C2 - 39500322

AN - SCOPUS:85210103835

SN - 0092-8674

VL - 187

SP - 7533-7550.e23

JO - Cell

JF - Cell

IS - 26

ER -

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

Abstract

Keywords

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