title: Chronic hepatitis C infection-induced liver fibrogenesis is associated with M2 macrophage activation.
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.
authors.affiliation: Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Moses T
authors.initials: MT
authors.lastname: Bility
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Kouki
authors.initials: K
authors.lastname: Nio
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: McGivern
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Division of Infectious Diseases, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Lemon
authors.affiliation: University College Dublin, Dublin, Ireland, USA.|Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Eoin R
authors.initials: ER
authors.lastname: Feeney
authors.affiliation: Massachusetts General Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Lishan
authors.initials: L
authors.lastname: Su
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D016174:Hepacivirus; D055166:Hepatic Stellate Cells / Q000166:cytology; D019698:Hepatitis C, Chronic / Q000150:complications / Q000473:pathology*; D006801:Humans; D007107:Immune System; D007249:Inflammation; D008099:Liver / Q000503:physiopathology / Q000821:virology; D008103:Liver Cirrhosis / Q000150:complications / Q000473:pathology*; D008262:Macrophage Activation; D008264:Macrophages / Q000166:cytology*; D051379:Mice
chemical_list: D000998:Antiviral Agents