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

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

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. VIDEO ABSTRACT: