UMMS Affiliation

Department of Medicine, Division of Gastroenterology; UMass Metabolic Network

Date

1-8-2016

Document Type

Article

Disciplines

Cell Biology | Cellular and Molecular Physiology | Gastroenterology | Hepatology | Immunology and Infectious Disease | Molecular Biology

Abstract

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.

Rights and Permissions

Copyright © 2016 The Authors. Citation: 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

Related Resources

Link to Article in PubMed

Keywords

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

PubMed ID

28090562

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

 
 

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