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

Abstract

SUMMARYTissue 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.

T Cells Infiltrating Diseased Liver Express Ligands for the NKG2D Stress Surveillance System

“…These, and other intrahepatic cells such as Kupffer cells, can also release reactive oxygen species (53), disrupting the local pro/antioxidant balance. Hepatic oxidative stress has been shown to drive viral hepatitis (54), including in a hepatitis B surface Ag transgenic mouse model (44). Studies in patients with CHB, in particular, staining of livers with HBV-related liver inflammation, also reveal features of oxidative stress (45, 55, 56).…”

Effects of Interferons and Viruses on Metabolism

“…Infection of mice with LCMV causes a dysregulation of the redox system in the liver. In this infection model, the early production of type I IFN causes tissue pathology due to the downregulation of superoxide dismutase 1 (Sod1) in the liver (117). Sod1 is a ubiquitously expressed antioxidative molecule, which can protect cells from oxidative stress by scavenging ${\text{O}}_2^{-}$ radicals (118) (Figure 3).…”

“…Hence, type I IFN-mediated oxidative stress may be a key mediator of virus-induced liver damage, and this suggests that early antioxidant treatment may be therapeutically helpful in ameliorating tissue damage. On the other hand, this oxidative stress, induced by the downregulation of Sod1, may also be part of an immediate antioxidant host defense system against pathogens (117). …”

Zika Virus Disease

“…IFN-1, binding to cellular receptors, mediates downregulation of the enzyme superoxide dismutase, the most powerful intracellular antioxidant. With respect to flavivirus-caused embryopathy, there is a deficit in knowledge (43).…”