Hepatitis C Virus-Induced Monocyte Differentiation Into Polarized M2 Macrophages Promotes Stellate Cell Activation via TGF-beta
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Document Type
Journal ArticlePublication Date
2016-01-08Keywords
APCantigen-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
Cell Biology
Cellular and Molecular Physiology
Gastroenterology
Hepatology
Immunology and Infectious Disease
Molecular Biology
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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.Source
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 siteDOI
10.1016/j.jcmgh.2015.12.005Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36728PubMed ID
28090562Related Resources
Link to Article in PubMedRights
Copyright © 2016 The Authors.Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.jcmgh.2015.12.005