VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium.
VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Laboratory for ER Stress and Inflammation, VIB-UniversityGent Center for Inflammation Research, Ghent 9052, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent 9000, Belgium.
Cell Host Microbe. 2024 Oct 9;32(10):1725-1743.e7. doi: 10.1016/j.chom.2024.08.007. Epub 2024 Sep 6.
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.
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，我们表明 TNF 限制了潘氏细胞 (PC) 的抗菌活性，导致细菌从肠道转移到各种器官。在 TNF 受体 P55 特异性缺失的 PC 小鼠中，不会发生这种 TNF 诱导的致死性。在 PCs 中，TNF 刺激 IFN 途径并消除稳态未折叠蛋白反应 (UPR)，在缺乏 P55 或 IFNAR1 的小鼠中未观察到这些作用。TNF 触发 IRE1 关键基因 Ern1 和 Ern2 的转录下调，这些基因是 UPR 的关键介质。这种 UPR 缺陷导致抗菌肽产生和 PC 抗菌活性显著减少，导致细菌易位到器官，随后发生多微生物败血症、器官衰竭和死亡。本研究强调了 PCs 在细菌控制和败血症治疗靶点中的作用。
