Viral hepatitis is a primary cause of mortality due to liver diseases worldwide. It manifests with a complex pathogenesis that involves immune-related events and altered cellular and tissue homeostasis, both of which eventually drive liver damage.
The immunological response of the host to the viral infection involves various cellular populations and mediators. The altered cellular homeostasis, on the other hand, refers to disruptions in the physiological state of the cell. This includes, for example, an imbalance in the cellular redox state, a consequence of which would be oxidative stress. One of the important factors implicated in the pathology of viral hepatitis is oxidative stress. However, there are several aspects till date that are not clearly understood, for example, what molecular mechanisms are responsible for initiating oxidative stress and what roles do the host anti-oxidative systems such as superoxide dismutases (SODs) play in protecting the host from liver damage. We describe a new concept of how type I interferon (IFN-I), a branch of the innate immune system induces oxidative stress and subsequently liver damage. We further identified the key antioxidant enzyme superoxide dismutase 1 (SOD1) as an essential host factor that prevented oxidative stress and hepatitis. Upon viral infection of the liver, we observed dysregulation of redox pathways, which included downregulation of SOD1. Sod1-/- mice suffered from exacerbated hepatitis compared to wild type mice post viral infection, which was ameliorated upon administration of antioxidant. Type I interferon (IFN-I) downregulated Sod1 in wild type mice on a transcriptional level and was sufficient to cause oxidative damage in the livers of Sod1-/- and wild type mice in the absence of infection. Moreover, both WT and Sod1-/- mice were protected against virus-induced hepatitis upon blocking IFN-I signaling.
These results provide a new concept of innate immunity-driven immunopathology, connecting IFN-I signaling with redox homeostasis and tissue damage.