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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.

Original publication

DOI

10.1016/j.immuni.2015.10.013

Type

Journal article

Journal

Immunity

Publication Date

11/2015

Volume

43

Pages

974 - 986

Addresses

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria.

Keywords

Liver, Killer Cells, Natural, T-Lymphocytes, Hepatocytes, Animals, Mice, Inbred C57BL, Mice, Hepatitis, Viral, Animal, Inflammation, Superoxide Dismutase, Interferon Type I, Antioxidants, Signal Transduction, Transcription, Genetic, Oxidation-Reduction, Oxidative Stress, Immunity, Innate, Superoxide Dismutase-1