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

IF 5.7 1区化学 Q2 CHEMISTRY, PHYSICAL

Journal of Chemical Theory and Computation Pub Date : 2024-11-04 DOI:10.1016/j.cell.2024.10.010

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, Ivan Zanoni

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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.

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III 型干扰素诱导肠道上皮细胞发生脓毒症并损害粘膜修复

组织损伤和修复是炎症的标志。尽管有大量关于组织损伤机制的信息，但对炎症如何影响修复的机制还缺乏深入了解。在这里，我们研究了干扰素如何影响肠粘膜损伤后的组织修复。我们发现，III 型而非 I 型或 II 型干扰素会通过诱导 Z-DNA 结合蛋白 1（ZBP1）的上调来延迟上皮细胞的再生。肠道损伤后形成的 Z 核酸会被 ZBP1 感知，从而导致 caspase-8 激活和 gasdermin C（GSDMC）的裂解。裂解后的 GSDMC 会导致上皮细胞热解死亡，并分别延缓结肠炎或辐照后大肠或小肠的修复。III 型干扰素/ZBP1/caspase-8/GSDMC 轴在炎症性肠病（IBD）患者中也很活跃。我们的研究结果突显了 III 型干扰素延迟肠道修复的能力，这对 IBD 患者或接受放射治疗的个体具有重要意义。

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来源期刊

Journal of Chemical Theory and Computation 化学-物理：原子、分子和化学物理

CiteScore

9.90

自引率

16.40%

发文量

568

审稿时长

1 months

期刊介绍： The Journal of Chemical Theory and Computation invites new and original contributions with the understanding that, if accepted, they will not be published elsewhere. Papers reporting new theories, methodology, and/or important applications in quantum electronic structure, molecular dynamics, and statistical mechanics are appropriate for submission to this Journal. Specific topics include advances in or applications of ab initio quantum mechanics, density functional theory, design and properties of new materials, surface science, Monte Carlo simulations, solvation models, QM/MM calculations, biomolecular structure prediction, and molecular dynamics in the broadest sense including gas-phase dynamics, ab initio dynamics, biomolecular dynamics, and protein folding. The Journal does not consider papers that are straightforward applications of known methods including DFT and molecular dynamics. The Journal favors submissions that include advances in theory or methodology with applications to compelling problems.