Department of Medicine, Division of Gastroenterology; UMass Metabolic Network
Cell Biology | Cellular and Molecular Physiology | Gastroenterology | Hepatology | Immunology and Infectious Disease | Molecular Biology
BACKGROUND and AIMS: Monocyte and macrophage (MPhi) activation contributes to the pathogenesis of chronic hepatitis C virus (HCV) infection. Disease pathogenesis is regulated by both liver-resident MPhis and monocytes recruited as precursors of MPhis into the damaged liver. Monocytes differentiate into M1 (classic/proinflammatory) or M2 (alternative/anti-inflammatory) polarized MPhis in response to tissue microenvironment. We hypothesized that HCV-infected hepatoma cells (infected with Japanese fulminant hepatitis-1 [Huh7.5/JFH-1]) induce monocyte differentiation into polarized MPhis.
METHODS: Healthy human monocytes were co-cultured with Huh7.5/JFH-1 cells or cell-free virus for 7 days and analyzed for MPhi markers and cytokine levels. A similar analysis was performed on circulating monocytes and liver MPhis from HCV-infected patients and controls.
RESULTS: Huh7.5/JFH-1 cells induced monocytes to differentiate into MPhis with increased expression of CD14 and CD68. HCV-MPhis showed M2 surface markers (CD206, CD163, and Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN)) and produced both proinflammatory and anti-inflammatory cytokines. HCV-induced early interleukin 1beta production promoted transforming growth factor (TGF)beta production and MPhi polarization to an M2 phenotype. TGF-beta secreted by M2-MPhi led to hepatic stellate cell activation indicated by increased expression of collagen, tissue inhibitor of metalloproteinase 1, and alpha-smooth muscle actin. In vivo, we observed a significant increase in M2 marker (CD206) expression on circulating monocytes and in the liver of chronic HCV-infected patients. Furthermore, we observed the presence of a unique collagen-expressing CD14+CD206+ monocyte population in HCV patients that correlated with liver fibrosis.
CONCLUSIONS: We show an important role for HCV in induction of monocyte differentiation into MPhis with a mixed M1/M2 cytokine profile and M2 surface phenotype that promote stellate cell activation via TGF-beta. We also identified circulating monocytes expressing M2 marker and collagen in chronic HCV infection that can be explored as a biomarker.
APC, antigen-presenting cell, Biomarkers, CD206, COL, collagen, Collagen, FITC, fluorescein isothiocyanate, Fibrocytes, HCV, hepatitis C virus, HSC, hepatic stellate cell, Huh7.5/JFH-1, Huh7.5 cells infected with JFH-1 (HCV), IL, interleukin, IL1RA, IL1-receptor antagonist, JFH-1, Japanese fulminant hepatitis-1, MFI, mean fluorescence intensity, MΦ, macrophage, NEAA, nonessential amino acid, PBMC, peripheral blood mononuclear cell, PE, Phycoerythrin, TGF, transforming growth factor, TIMP, tissue inhibitor of metalloproteinase, TNF, tumor necrosis factor, mRNA, messenger RNA, α-SMA, α-smooth muscle actin
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DOI of Published Version
Cell Mol Gastroenterol Hepatol. 2016 Jan 8;2(3):302-316.e8. 10.1016/j.jcmgh.2015.12.005. eCollection 2016 May. Link to article on publisher's site
Cellular and molecular gastroenterology and hepatology
Saha B, Kodys K, Szabo G. (2016). Hepatitis C Virus-Induced Monocyte Differentiation Into Polarized M2 Macrophages Promotes Stellate Cell Activation via TGF-beta. UMass Metabolic Network Publications. https://doi.org/10.1016/j.jcmgh.2015.12.005. Retrieved from https://escholarship.umassmed.edu/metnet_pubs/95
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