The Pannexin 1/Purinergic Receptor P2X4 Pathway Controls the Secretion of MicroRNA-Containing Exosomes by HCV-Infected Hepatocytes.

BACKGROUND AND AIMS: HCV infection is a major risk factor that can lead to chronic liver disease, including fibrosis, cirrhosis, and HCC. Progression of chronic liver disease by HCV infection is caused by a complex intercellular reaction. Especially, exosomes and microRNAs (miRNAs) from HCV-infected hepatocytes play a role in the pathogenesis of liver disease by facilitating cellular communication between parenchymal and nonparenchymal cells. However, the underlying mechanism of secretions of exosome and miRNAs during HCV infection is still open for study. APPROACH AND RESULTS: In this study, we demonstrated a pathway for the release of exosome and exosomal miRNAs through caspase-3/pannexin 1 (Panx1)/P2X4 activation during HCV infection in hepatocytes. We found that HCV infection induced the stimulation of exosome release and activation of the caspase-3/Panx1/P2X4 pathway in Huh7.5.1 cells. In addition, miR-122 and miR-146a levels in extracellular exosomes from HCV-infected cells were dramatically increased whereas intracellular miR122 and miR-146a expression had no large changes. Notably, secretions of exosomes and exosomal miRNAs were decreased by inhibition of caspase 3, Panx1, and P2X4 whereas inhibition of ROCK-1 cleavage did not affect these during HCV infection in Huh7.5.1 cells. CONCLUSIONS: These results suggested that HCV infection caused secretions of exosomes and exosomal miRNAs dependent on the caspase 3/Panx1/P2X4 pathway. Our study provides a possible therapeutic intervention using Panx1 suppression for liver disease development mediated by exosomes from HCV-infected hepatocytes.