Modulation of calcium signaling pathway by hepatitis C virus core protein stimulates NLRP3 inflammasome activation

Hepatitis C virus (HCV) infection remains a major cause of hepatic inflammation and liver disease. HCV triggers NLRP3 inflammasome activation and interleukin-1 (IL-1) production from hepatic macrophages, or Kupffer cells, to drive the hepatic inflammatory response. Here we examined HCV activation of the NLRP3 inflammasome signaling cascade in primary human monocyte derived macrophages and THP-1 cell models of hepatic macrophages to define the HCV-specific agonist and cellular processes of inflammasome activation. We identified the HCV core protein as a virion-specific factor of inflammasome activation. The core protein was both necessary and sufficient for IL-1 production from macrophages exposed to HCV or soluble core protein alone. NLRP3 inflammasome activation by the HCV core protein required calcium mobilization linked with phospholipase-C activation. Our findings reveal a molecular basis of hepatic inflammasome activation and IL-1 release triggered by HCV core protein. Author summary This study deciphers the molecular mechanism of Hepatitis C virus (HCV)-induced hepatic inflammation. HCV triggers NLRP3 inflammasome activation and IL-1 release from hepatic macrophages, thus driving liver inflammation. Using biochemical, virological, and genetic approaches we identified the HCV core protein as the specific viral stimulus that triggers intracellular calcium signaling linked with phospholipase-C activation to drive NLRP3 inflammasome activation and IL-1 release in macrophages.