Paneth 细胞 TNF 信号诱导肠道细菌迁移和败血症

IF 20.6 1区 医学 Q1 MICROBIOLOGY Cell host & microbe Pub Date : 2024-09-06 DOI:10.1016/j.chom.2024.08.007
Charlotte Wallaeys, Natalia Garcia-Gonzalez, Steven Timmermans, Jolien Vandewalle, Tineke Vanderhaeghen, Somara De Beul, Hester Dufoor, Melanie Eggermont, Elise Moens, Victor Bosteels, Riet De Rycke, Fabien Thery, Francis Impens, Serge Verbanck, Stefan Lienenklaus, Sophie Janssens, Richard S. Blumberg, Takao Iwawaki, Claude Libert
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引用次数: 0

摘要

细胞因子肿瘤坏死因子(TNF)在限制感染方面发挥着重要作用,但也与败血症有关。这些矛盾作用的机制尚不清楚。在这里,我们发现 TNF 限制了 Paneth 细胞(PCs)的抗菌活性,导致细菌从肠道转移到各个器官。这种 TNF 诱导的致死现象不会发生在 TNF 受体 P55 PC 特异性缺失的小鼠身上。在 PC 中,TNF 可刺激 IFN 通路并消除稳态未折叠蛋白反应(UPR),而在缺乏 P55 或 IFNAR1 的小鼠中却观察不到这种效应。TNF 触发 IRE1 关键基因 Ern1 和 Ern2 的转录下调,而 Ern1 和 Ern2 是 UPR 的关键介质。这种 UPR 缺乏会导致抗菌肽的产生和 PC 的抗菌活性显著降低,从而引起细菌向器官转移,继而导致多微生物败血症、器官衰竭和死亡。这项研究强调了 PC 在细菌控制中的作用以及败血症的治疗靶点。
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Paneth cell TNF signaling induces gut bacterial translocation and sepsis

The cytokine tumor necrosis factor (TNF) plays important roles in limiting infection but is also linked to sepsis. The mechanisms underlying these paradoxical roles are unclear. Here, we show that TNF limits the antimicrobial activity of Paneth cells (PCs), causing bacterial translocation from the gut to various organs. This TNF-induced lethality does not occur in mice with a PC-specific deletion in the TNF receptor, P55. In PCs, TNF stimulates the IFN pathway and ablates the steady-state unfolded protein response (UPR), effects not observed in mice lacking P55 or IFNAR1. TNF triggers the transcriptional downregulation of IRE1 key genes Ern1 and Ern2, which are key mediators of the UPR. This UPR deficiency causes a significant reduction in antimicrobial peptide production and PC antimicrobial activity, causing bacterial translocation to organs and subsequent polymicrobial sepsis, organ failure, and death. This study highlights the roles of PCs in bacterial control and therapeutic targets for sepsis.

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来源期刊
Cell host & microbe
Cell host & microbe 生物-微生物学
CiteScore
45.10
自引率
1.70%
发文量
201
审稿时长
4-8 weeks
期刊介绍: Cell Host & Microbe is a scientific journal that was launched in March 2007. The journal aims to provide a platform for scientists to exchange ideas and concepts related to the study of microbes and their interaction with host organisms at a molecular, cellular, and immune level. It publishes novel findings on a wide range of microorganisms including bacteria, fungi, parasites, and viruses. The journal focuses on the interface between the microbe and its host, whether the host is a vertebrate, invertebrate, or plant, and whether the microbe is pathogenic, non-pathogenic, or commensal. The integrated study of microbes and their interactions with each other, their host, and the cellular environment they inhabit is a unifying theme of the journal. The published work in Cell Host & Microbe is expected to be of exceptional significance within its field and also of interest to researchers in other areas. In addition to primary research articles, the journal features expert analysis, commentary, and reviews on current topics of interest in the field.
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