NOX1-NOS2 活性失调是小鼠回肠炎的标志。

IF 7.9 2区 医学 Q1 IMMUNOLOGY Mucosal Immunology Pub Date : 2024-09-07 DOI:10.1016/j.mucimm.2024.08.012
Julie Drieu La Rochelle, Josie Ward, Emily Stenke, Yuting Yin, Misaki Matsumoto, Richard Jennings, Gabriella Aviello, Ulla G Knaus
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引用次数: 0

摘要

回肠炎症或回肠炎通常由克罗恩病(CD)引起,但也可能伴随溃疡性结肠炎(反冲洗性回肠炎)、感染或药物相关损伤。活性氧(ROS)引发的氧化性组织损伤被认为是回肠炎病因的一部分。然而,炎症性肠病(IBD)不仅与 ROS 升高有关,还与 ROS 长期减少有关。虽然极早发 IBD(VEO-IBD)与一系列 NOX1 变体有关,但 NOX1 失活如何导致疾病发展仍未明确。除了传播信号反应外,NOX1 还为上皮屏障中过亚硝酸盐的形成提供超氧化物。在这里,我们报告了 NOX4(一种产生 H2O2 的 NADPH 氧化酶,在肠道和其他组织中具有有据可查的组织保护作用)限制了 NOX1/NOS2 产生回肠过亚硝酸盐。缺失 NOX4 会导致持续的过亚硝酸盐过量、高渗透性、绒毛变钝、肌肉肥大、趋化因子/细胞因子上调和菌群失调。相反,SAMP1/YitFc 小鼠(一种类似 CD 的回肠炎模型)表现出年龄依赖性 NOX1/NOS2 下调,从而防止了在平衡状态和 LPS 诱导的急性炎症中回肠过氧亚硝酸盐的形成。NOX1 的缺失与抗菌肽的上调有关,这表明回肠过氧亚硝酸盐在回肠中起着化学屏障和微生物群调节剂的作用。
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Dysregulated NOX1-NOS2 activity as hallmark of ileitis in mice.

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 H2O2-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.

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来源期刊
Mucosal Immunology
Mucosal Immunology 医学-免疫学
CiteScore
16.60
自引率
3.80%
发文量
100
审稿时长
12 days
期刊介绍: Mucosal Immunology, the official publication of the Society of Mucosal Immunology (SMI), serves as a forum for both basic and clinical scientists to discuss immunity and inflammation involving mucosal tissues. It covers gastrointestinal, pulmonary, nasopharyngeal, oral, ocular, and genitourinary immunology through original research articles, scholarly reviews, commentaries, editorials, and letters. The journal gives equal consideration to basic, translational, and clinical studies and also serves as a primary communication channel for the SMI governing board and its members, featuring society news, meeting announcements, policy discussions, and job/training opportunities advertisements.
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