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Immunity. 2015 Nov 17;43(5):974-86. doi: 10.1016/j.immuni.2015.10.013.

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

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria.
2
Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Institute, 10117 Berlin, Germany; Translational Gastroenterology Unit, Experimental Medicine Division Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, UK.
3
Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany.
4
Institute of Immunobiology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland.
5
Department of Pathology and Immunology, University of Geneva, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva, Switzerland; Department of Neuropathology, University Medicine Göttingen, Robert-Koch Strasse 40, 37099 Goettingen, Germany.
6
Department of Medicine I for Gastroenterology, Infectious Disease and Rheumatology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.
7
Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Institute, 10117 Berlin, Germany.
8
Translational Gastroenterology Unit, Experimental Medicine Division Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, UK.
9
Department of Gastroenterology, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.
10
Department of Gastroenterology, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany; Department of Molecular Medicine II, Heinrich Heine University, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
11
Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109-5219, USA.
12
Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan.
13
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria; Center for Physiology and Pharmacology, Medical University of Vienna, Lazarettgasse 14, 1090 Vienna, Austria.
14
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria. Electronic address: abergthaler@cemm.oeaw.ac.at.

Abstract

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.

PMID:
26588782
PMCID:
PMC4658338
DOI:
10.1016/j.immuni.2015.10.013
[Indexed for MEDLINE]
Free PMC Article

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