Mechanism of hepatic inflammation during hepatitis C virus infection

Abstract

Chronic hepatitis C virus (HCV) infection is a leading cause of liver disease. Liver inflammation underlies infection-induced fibrosis, cirrhosis and liver cancer, but the processes that promote hepatic inflammation by HCV are not defined. We used a systems biology analysis together with multiple lines of evidence to demonstrate that interleukin-1&beta (IL-1&beta) production by intrahepatic macrophages confers liver inflammation through HCV-induced inflammasome signaling. Chronic hepatitis C patients exhibited elevated levels of serum IL-1&beta compared to healthy controls. Immunohistochemical analysis of healthy control and chronic hepatitis C liver sections revealed that Kupffer cells- resident hepatic macrophages- are the primary cellular source of hepatic IL-1&beta during HCV infection. Accordingly, we found that both blood monocyte-derived primary human macrophages and Kupffer cells recovered from normal donor liver produce IL-1&beta after HCV exposure. Using the THP-1 macrophage cell-culture model, we found that HCV drives a rapid but transient caspase-1 activation to stimulate IL-1&beta processing and secretion. HCV can enter macrophages through non-CD81 mediated phagocytic uptake that is independent of productive infection. Viral RNA triggered the MyD88-mediated TLR7 signaling pathway to induce IL-1&beta mRNA expression. HCV uptake concomitantly induced a potassium efflux that activated the NLRP3 inflammasome for IL-1&beta processing and secretion. RNA sequencing analysis comparing THP1 cells and liver samples from chronic hepatitis C virus-infected patients revealed that viral engagement of the NLRP3 inflammasome stimulates IL-1&beta production to drive proinflammatory cytokine, chemokine, and immune-regulatory gene expression networks linked with HCV disease severity. These studies identified intrahepatic IL-17beta production as a central feature of liver inflammation during HCV infection. Thus, strategies to suppress NLRP3 or IL-1&beta activity could offer therapeutic approaches to reduce hepatic inflammation and mitigate disease.