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Cited by 65Liver physiology and pathologyHepatitis C virus researchImmune cells in cancer

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Hepatitis C Virus-Induced Monocyte Differentiation Into Polarized M2 Macrophages Promotes Stellate Cell Activation via TGF-β

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Saha, Banishree, Kodys, Karen, Szabo, Gyongyi·2016·Cellular and Molecular Gastroenterology and Hepatology
DOI 10.1016/j.jcmgh.2015.12.005PMC PMC5042356
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Abstract

Background & Aims Monocyte and macrophage (MΦ) activation contributes to the pathogenesis of chronic hepatitis C virus (HCV) infection. Disease pathogenesis is regulated by both liver-resident MΦs and monocytes recruited as precursors of MΦs into the damaged liver. Monocytes differentiate into M1 (classic/proinflammatory) or M2 (alternative/anti-inflammatory) polarized MΦs 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 MΦs. Methods Healthy human monocytes were co-cultured with Huh7.5/JFH-1 cells or cell-free virus for 7 days and analyzed for MΦ markers and cytokine levels. A similar analysis was performed on circulating monocytes and liver MΦs from HCV-infected patients and controls. Results Huh7.5/JFH-1 cells induced monocytes to differentiate into MΦs with increased expression of CD14 and CD68. HCV-MΦs 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 1β production promoted transforming growth factor (TGF)β production and MΦ polarization to an M2 phenotype. TGF-β secreted by M2-MΦ led to hepatic stellate cell activation indicated by increased expression of collagen, tissue inhibitor of metalloproteinase 1, and α-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 MΦs with a mixed M1/M2 cytokine profile and M2 surface phenotype that promote stellate cell activation via TGF-β. We also identified circulating monocytes expressing M2 marker and collagen in chronic HCV infection that can be explored as a biomarker.

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  • In chronic viral hepatitis or parasitic infections, excessive anti-inflammatory polarization may impair pathogen clearance and perpetuate chronic inflammation.

    “In these settings, excessive anti-inflammatory polarization may impair pathogen clearance and perpetuate chronic inflammation, thereby reshaping macrophage function (129–135).”

    From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [134]

    The Introduction and Discussion (pages unavailable in our copy) describe M2-like anti-inflammatory polarization during chronic HCV infection and link HCV-induced macrophage changes to liver fibrosis. They do not establish that this polarization impairs pathogen clearance or address parasitic infections. (LLM, conf=0.85)

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Metadata

Authors
Saha, B., Kodys, K., & Szabo, G.
Affiliations
University of Massachusetts Chan Medical School (US)
ORCID
Saha, Banishree
Venue
Cellular and Molecular Gastroenterology and Hepatology
Publisher
Elsevier BV
Published
2016-05
Volume
2
Issue
3
Pages
302-316.e8
ISSN
2352-345X (ISSN-L)
DOI
10.1016/j.jcmgh.2015.12.005
PMC
PMC5042356
OpenAlex
W2289398048
Cited by
65
References
0
Citations by year
2026: 7 · 2025: 5 · 2024: 4 · 2023: 2 · 2022: 10 · 2021: 7 · 2020: 9 · 2019: 8 · 2018: 2 · 2017: 9 · 2016: 1
FWCI
4.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Gastroenterology and Hepatology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • National Institute on Alcohol Abuse and Alcoholism (R37AA014372)
  • NIH Clinical Center
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Hepatitis C virus research
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
hepatitis C virus, monocyte differentiation, M2 macrophages, macrophage polarization, hepatic stellate cell activation, TGF-beta, IL-1β, liver fibrosis, chronic hepatitis C, CD206, circulating monocytes, macrophage markers, collagen, TIMP-1

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