title: M2 Macrophages Play Critical Roles in Progression of Inflammatory Liver Disease in Hepatitis C Virus Transgenic Mice.
abstract: Macrophages in liver tissue are widely defined as important inflammatory cells in chronic viral hepatitis due to their proinflammatory activity. We reported previously that interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) play significant roles in causing chronic hepatitis in hepatitis C virus (HCV) transgenic mice (S. Sekiguchi et al., PLoS One 7:e51656, 2012, http://dx.doi.org/10.1371/journal.pone.0051656). In addition, we showed that recombinant vaccinia viruses expressing an HCV nonstructural protein (rVV-N25) could protect against the progression of chronic hepatitis by suppression of macrophage activation. Here, we focus on the role of macrophages in liver disease progression in HCV transgenic mice and examine characteristic features of macrophages following rVV-N25 treatment. The number of CD11b(+) F4/80(+) CD11c(-) CD206(+) (M2) macrophages in the liver of HCV transgenic mice was notably increased compared to that of age-matched control mice. These M2 macrophages in the liver produced elevated levels of IL-6 and TNF-α. rVV-N25 infection suppressed the number and activation of M2 macrophages in liver tissue. These results suggested that inflammatory cytokines produced by M2-like macrophages contribute to the induction of chronic liver inflammation in HCV transgenic mice. Moreover, the therapeutic effect of rVV-N25 might be induced by the suppression of the number and activation of hepatic macrophages.
  
  
  OBJECTIVE
  HCV causes persistent infections that can lead to chronic liver diseases, liver fibrosis, and hepatocellular carcinoma; the search for an HCV curative is the focus of ongoing research. Recently, effective anti-HCV drugs have been developed; however, vaccine development still is required for the prevention and therapy of infection by this virus. We demonstrate here that M2 macrophages are important for the pathogenesis of HCV-caused liver diseases and additionally show that M2 macrophages contribute to the therapeutic mechanism observed following rVV-N25 treatment.
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa, Setagaya-ku, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ohtsuki
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa, Setagaya-ku, Tokyo, Japan Division of Hepatology, Tokyo Metropolitan Komagome Hospital, Honkomagome, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kiminori
authors.initials: K
authors.lastname: Kimura
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa, Setagaya-ku, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tokunaga
authors.affiliation: Transboundary Animal Diseases Center, Joint Faculty of Veterinary Medicine, Kagoshima University, Korimoto Kagoshima, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Tsukiyama-Kohara
authors.affiliation: PhoenixBio Co., Ltd., Kagamiyama, Higashi-Hiroshima, Japan.
authors.forename: Chise
authors.initials: C
authors.lastname: Tateno
authors.affiliation: Department of Pathology, Tokyo Metropolitan Komagome Hospital, Honkomagome, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Department of Pathology, Tokyo Metropolitan Komagome Hospital, Honkomagome, Bunkyo-ku, Tokyo, Japan.
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Hishima
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa, Setagaya-ku, Tokyo, Japan kohara-mc@igakuken.or.jp.
authors.forename: Michinori
authors.initials: M
authors.lastname: Kohara
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000473:pathology* / Q000821:virology; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D008822:Mice, Transgenic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha