Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage.
Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage.
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DOI：
10.1016/j.immuni.2015.10.013
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发表时间：
2015-11-17
期刊：
影响因子：
32.4
通讯作者：
Bergthaler A
中科院分区：
文献类型：
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作者：
Bhattacharya A;Hegazy AN;Deigendesch N;Kosack L;Cupovic J;Kandasamy RK;Hildebrandt A;Merkler D;Kühl AA;Vilagos B;Schliehe C;Panse I;Khamina K;Baazim H;Arnold I;Flatz L;Xu HC;Lang PA;Aderem A;Takaoka A;Superti-Furga G;Colinge J;Ludewig B;Löhning M;Bergthaler A
病毒性肝炎引起的组织损伤是世界范围内发病率和死亡率的主要原因。使用病毒性肝炎的小鼠模型，我们确定了肝脏氧化还原途径中病毒诱导的早期转录变化，包括超氧化物歧化酶1（Sod 1）的下调。Sod 1 −/−小鼠在病毒感染后表现出炎症增加和肝损伤加重，这与T细胞和NK细胞无关，可以通过抗氧化剂治疗来改善。I型干扰素（IFN-I）导致Sod 1下调，并在Sod 1 −/−和野生型小鼠中引起氧化性肝损伤。基因和药理学阻断IFN-I信号通路可防止病毒诱导的肝损伤这些结果描述了IFN-I介导的氧化应激作为病毒诱导的肝损伤的关键介质，并描述了先天免疫驱动的病理机制，将IFN-I信号传导与抗氧化宿主防御和感染相关的组织损伤联系起来。病毒感染导致氧化还原失调，包括SOD 1的下调Sod 1 −/−小鼠表现出加重的病毒性肝炎，通过STAT 1驱动SOD 1下调和早期肝损伤的抗氧化剂IFN-I信号传导的拯救IFN-I信号传导的消融改善Sod 1 −/−和WT小鼠的病毒性肝炎Bergthaler和同事表明，超氧化物歧化酶1保护肝脏免受I型干扰素的侵害。导致病毒性肝炎的氧化损伤。肝损伤由肝细胞内源性IFNAR 1-STAT 1信号转导介导。
Tissue damage caused by viral hepatitis is a major cause of morbidity and mortality worldwide. Using a mouse model of viral hepatitis, we identified virus-induced early transcriptional changes in the redox pathways in the liver, including downregulation of superoxide dismutase 1 (Sod1). Sod1−/− mice exhibited increased inflammation and aggravated liver damage upon viral infection, which was independent of T and NK cells and could be ameliorated by antioxidant treatment. Type I interferon (IFN-I) led to a downregulation of Sod1 and caused oxidative liver damage in Sod1−/− and wild-type mice. Genetic and pharmacological ablation of the IFN-I signaling pathway protected against virus-induced liver damage. These results delineate IFN-I mediated oxidative stress as a key mediator of virus-induced liver damage and describe a mechanism of innate-immunity-driven pathology, linking IFN-I signaling with antioxidant host defense and infection-associated tissue damage. Viral infection leads to redox dysregulation including the downregulation of SOD1 Sod1 −/− mice exhibit aggravated viral hepatitis, which is rescued by antioxidants IFN-I signaling via STAT1 drives SOD1 downregulation and early liver damage Ablation of IFN-I signaling ameliorates viral hepatitis in Sod1 −/− and WT mice Bergthaler and colleagues show that superoxide dismutase 1 protects the liver from type I interferon-driven oxidative damage in viral hepatitis. Liver damage was mediated by hepatocyte-intrinsic IFNAR1-STAT1 signaling.