Dysregulated NOX1-NOS2 activity as hallmark of ileitis in mice.

Autor: Drieu La Rochelle J; UCD Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland., Ward J; UCD Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland., Stenke E; UCD Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland., Yin Y; UCD Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland., Matsumoto M; Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto, Japan., Jennings R; UCD Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland., Aviello G; Department of Pharmacy, University of Naples Federico II, Naples, Italy., Knaus UG; UCD Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland. Electronic address: ulla.knaus@ucd.ie.
Jazyk: angličtina
Zdroj: Mucosal immunology [Mucosal Immunol] 2024 Dec; Vol. 17 (6), pp. 1326-1336. Date of Electronic Publication: 2024 Sep 07.
DOI: 10.1016/j.mucimm.2024.08.012
Abstrakt: Inflammation of the ileum, or ileitis, is commonly caused by Crohn's disease (CD) but can also accompany ulcerative colitis (backwash ileitis), infections or drug-related damage. Oxidative tissue injury triggered by reactive oxygen species (ROS) is considered part of the ileitis etiology. However, not only elevated ROS but also permanently decreased ROS are associated with inflammatory bowel disease (IBD). While very early onset IBD (VEO-IBD) is associated with a spectrum of NOX1 variants, how NOX1 inactivation contributes to disease development remains ill-defined. Besides propagating signaling responses, NOX1 provides superoxide for peroxynitrite formation in the epithelial barrier. Here we report that NOX4, an H 2 O 2 -generating NADPH oxidase with documented tissue protective effects in the intestine and other tissues, limits the generation of ileal peroxynitrite by NOX1/NOS2. Deletion of NOX4 leads to persistent peroxynitrite excess, hyperpermeability, villus blunting, muscular hypertrophy, chemokine/cytokine upregulation and dysbiosis. Conversely, SAMP1/YitFc mice, a CD-like ileitis model, showed age-dependent NOX1/NOS2 downregulation preventing ileal peroxynitrite formation in homeostasis and LPS-induced acute inflammation. Deficiency in NOX1 correlated with the upregulation of antimicrobial peptides, suggesting that ileal peroxynitrite acts as chemical barrier and microbiota modifier in the ileum.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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