Chronic hepatitis C infection-induced liver fibrogenesis is associated with M2 macrophage activation

Sci Rep. 2016 Dec 21;6:39520. doi: 10.1038/srep39520.

Abstract

The immuno-pathogenic mechanisms of chronic hepatitis C virus (HCV) infection remain to be elucidated and pose a major hurdle in treating or preventing chronic HCV-induced advanced liver diseases such as cirrhosis. Macrophages are a major component of the inflammatory milieu in chronic HCV-induced liver disease, and are generally derived from circulating inflammatory monocytes; however very little is known about their role in liver diseases. To investigate the activation and role of macrophages in chronic HCV-induced liver fibrosis, we utilized a recently developed humanized mouse model with autologous human immune and liver cells, human liver and blood samples and cell culture models of monocyte/macrophage and/or hepatic stellate cell activation. We showed that M2 macrophage activation was associated with liver fibrosis during chronic HCV infection in the livers of both humanized mice and patients, and direct-acting antiviral therapy attenuated M2 macrophage activation and associated liver fibrosis. We demonstrated that supernatant from HCV-infected liver cells activated human monocytes/macrophages with M2-like phenotypes. Importantly, HCV-activated monocytes/macrophages promoted hepatic stellate cell activation. These results suggest a critical role for M2 macrophage induction in chronic HCV-associated immune dysregulation and liver fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Chronic Disease
  • Disease Models, Animal
  • Hepacivirus
  • Hepatic Stellate Cells / cytology
  • Hepatitis C, Chronic / complications
  • Hepatitis C, Chronic / pathology*
  • Humans
  • Immune System
  • Inflammation
  • Liver / physiopathology
  • Liver / virology
  • Liver Cirrhosis / complications
  • Liver Cirrhosis / pathology*
  • Macrophage Activation*
  • Macrophages / cytology*
  • Mice

Substances

  • Antiviral Agents