Saha, BanishreeKodys, KarenSzabo, Gyongyi2022-08-232022-08-232016-01-082017-05-25Cell Mol Gastroenterol Hepatol. 2016 Jan 8;2(3):302-316.e8. 10.1016/j.jcmgh.2015.12.005. eCollection 2016 May. <a href="https://doi.org/10.1016/j.jcmgh.2015.12.005">Link to article on publisher's site</a>2352-345X (Linking)10.1016/j.jcmgh.2015.12.00528090562https://hdl.handle.net/20.500.14038/36728BACKGROUND 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.en-USCopyright © 2016 The Authors.http://creativecommons.org/licenses/by-nc-nd/4.0/APCantigen-presenting cellBiomarkersCD206COLcollagenCollagenFITCfluorescein isothiocyanateFibrocytesHCVhepatitis C virusHSChepatic stellate cellHuh7.5/JFH-1Huh7.5 cells infected with JFH-1 (HCV)ILinterleukinIL1RAIL1-receptor antagonistJFH-1Japanese fulminant hepatitis-1MFImean fluorescence intensityMΦmacrophageNEAAnonessential amino acidPBMCperipheral blood mononuclear cellPEPhycoerythrinTGFtransforming growth factorTIMPtissue inhibitor of metalloproteinaseTNFtumor necrosis factormRNAmessenger RNAα-SMAα-smooth muscle actinCell BiologyCellular and Molecular PhysiologyGastroenterologyHepatologyImmunology and Infectious DiseaseMolecular BiologyJournal Articlehttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1094&amp;context=metnet_pubs&amp;unstamped=1https://escholarship.umassmed.edu/metnet_pubs/9510212160metnet_pubs/95