Paneth cell TNF signaling induces gut bacterial translocation and sepsis.

Autor:	Wallaeys C; VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium., Garcia-Gonzalez N; VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium., Timmermans S; VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium., Vandewalle J; VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium., Vanderhaeghen T; VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium., De Beul S; VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium., Dufoor H; VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium., Eggermont M; VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium., Moens E; VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium., Bosteels V; 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., De Rycke R; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium; VIB Center for Inflammation Research and Bioimaging Core, VIB, Ghent 9052, Belgium., Thery F; VIB-UGent Center for Medical Biotechnology, VIB, Ghent 9052, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent 9052, Belgium., Impens F; VIB-UGent Center for Medical Biotechnology, VIB, Ghent 9052, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent 9052, Belgium; VIB Proteomics Core, VIB, Ghent 9052, Belgium., Verbanck S; Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke 9820, Belgium., Lienenklaus S; Institute of Laboratory Animal Science, Hannover Medical School, Hannover 30625, Germany., Janssens S; 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., Blumberg RS; Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA., Iwawaki T; Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan., Libert C; VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium. Electronic address: claude.libert@irc.vib-ugent.be.
Jazyk:	angličtina
Zdroj:	Cell host & microbe [Cell Host Microbe] 2024 Oct 09; Vol. 32 (10), pp. 1725-1743.e7. Date of Electronic Publication: 2024 Sep 06.
DOI:	10.1016/j.chom.2024.08.007
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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