Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage

• Published in: Immunity (Cambridge, Mass.) Vol. 43; no. 5; pp. 974 - 986
• Main Authors: Bhattacharya, Anannya, Hegazy, Ahmed N., Deigendesch, Nikolaus, Kosack, Lindsay, Cupovic, Jovana, Kandasamy, Richard K., Hildebrandt, Andrea, Merkler, Doron, Kühl, Anja A., Vilagos, Bojan, Schliehe, Christopher, Panse, Isabel, Khamina, Kseniya, Baazim, Hatoon, Arnold, Isabelle, Flatz, Lukas, Xu, Haifeng C., Lang, Philipp A., Aderem, Alan, Takaoka, Akinori, Superti-Furga, Giulio, Colinge, Jacques, Ludewig, Burkhard, Löhning, Max, Bergthaler, Andreas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.11.2015; Elsevier Limited; Elsevier; The Authors. Published by Elsevier Inc
• Subjects: Animals; Antioxidants; Antioxidants - metabolism; Biomedical research; Cloning; Colleges & universities; Enzymes; Experiments; Gene expression; Hepatitis, Viral, Animal - immunology; Hepatocytes - immunology; Human health and pathology; Immunity, Innate - immunology; Infections; Inflammation - immunology; Interferon Type I - immunology; Killer Cells, Natural - immunology; Life Sciences; Liver - immunology; Liver cancer; Mice; Mice, Inbred C57BL; Mortality; Oxidation-Reduction; Oxidative stress; Oxidative Stress - immunology; Pathogenesis; Pathology; Rodents; Scholarships & fellowships; Signal Transduction - immunology; Superoxide Dismutase - immunology; Superoxide Dismutase-1; T-Lymphocytes - immunology; Transcription, Genetic - immunology; Viral infections
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2015.10.013

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. [Display omitted] [Display omitted] •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.