Hepatitis C Virus Infection Induces Autocrine Interferon Signaling by Human Liver Endothelial Cells and Release of Exosomes, Which Inhibits Viral Replication

Giugliano, Silvia; Kriss, Michael; Golden-Mason, Lucy; Dobrinskikh, Evgenia; Stone, Amy E. L.; Soto-Gutiérrez, Alejandro; Mitchell, Angela M.; Khetani, Salman R.; Yamane, Daisuke; Stoddard, Mark B.; Li, Hui; Shaw, George M.; Edwards, Michael G.; Lemon, Stanley M.; Gale, Michael; Shah, Vijay H.; Rosen, Hugo R.

doi:10.1053/j.gastro.2014.10.040

Cited by 100 publications

(88 citation statements)

References 62 publications

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“…Liver cells stimulated by type I interferon (IFN) secrete exosomes, which contain antiviral molecules and can attenuate hepatitis B virus (HBV) replication (8). Exosomes isolated from liver endothelial cells stimulated by either type I or III IFNs can also suppress viral replication in HCV-infected liver cells (9). Recently, we have also shown the role of exosomes in HCV release from infected hepatocytes (10).…”

mentioning

confidence: 99%

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Devhare

Sasaki

Shrivastava

et al. 2017

J Virol

143

157

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Fibrogenic pathways in the liver are principally regulated by activation of hepatic stellate cells (HSC). Fibrosis is associated with chronic hepatitis C virus (HCV) infection, although the mechanism is poorly understood. HSC comprise the major population of nonparenchymal cells in the liver. Since HCV does not replicate in HSC, we hypothesized that exosomes secreted from HCV-infected hepatocytes activate HSC. Primary or immortalized human hepatic stellate (LX2) cells were exposed to exosomes derived from HCV-infected hepatocytes (HCV-exo), and the expression of fibrosis-related genes was examined. Our results demonstrated that HCV-exo internalized to HSC and increased the expression of profibrotic markers. Further analysis suggested that HCV-exo carry miR-19a and target SOCS3 in HSC, which in turn activates the STAT3-mediated transforming growth factor ␤ (TGF-␤) signaling pathway and enhances fibrosis marker genes. The higher expression of miR-19a in exosomes was also observed from HCV-infected hepatocytes and in sera of chronic HCV patients with fibrosis compared to healthy volunteers and non-HCV-related liver disease patients with fibrosis. Together, our results demonstrated that miR-19a carried through the exosomes from HCV-infected hepatocytes activates HSC by modulating the SOCS-STAT3 axis. Our results implicated a novel mechanism of exosome-mediated intercellular communication in the activation of HSC for liver fibrosis in HCV infection.IMPORTANCE HCV-associated liver fibrosis is a critical step for end-stage liver disease progression. However, the molecular mechanisms for hepatic stellate-cell activation by HCV-infected hepatocytes are underexplored. Here, we provide a role for miR-19a carried through the exosomes in intercellular communication between HCVinfected hepatocytes and HSC in fibrogenic activation. Furthermore, we demonstrate the role of exosomal miR-19a in activation of the STAT3-TGF-␤ pathway in HSC. This study contributes to the understanding of intercellular communication in the pathogenesis of liver disease during HCV infection. KEYWORDS hepatitis C virus, exosomes, miRNAs, liver fibrosis, hepatic stellate cells, microRNA H epatitis C virus (HCV) is a positive-sense, single-stranded RNA virus with a genome size of 9.6 kb that encodes several structural and nonstructural proteins. About 170 million people are infected with HCV worldwide. Chronic HCV infection often results in the development of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCVassociated liver fibrosis is a key pathological process leading to liver cirrhosis and HCC (1, 2), although the underlying mechanisms of disease progression remain unclear. Hepatic stellate cells (HSC) are involved in the pathogenesis of liver fibrosis (3). Liver injury is characterized by a phenotypic and functional transformation of normally

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mentioning

confidence: 99%

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Devhare

Sasaki

Shrivastava

et al. 2017

J Virol

143

157

View full text Add to dashboard Cite

show abstract

“…Liver cells stimulated by type I IFN, IFN-α secrete exosomes which contain antiviral molecules and can attenuate hepatitis B virus (HBV) replication [25]. Exosomes isolated from liver endothelial cells stimulated by either type I or III IFNs can also suppress viral replication in HCV-infected liver cells [26]. These findings suggest that both viral infection and antiviral response are mediated by cell-cell communication through exosomes.…”

Section: Cell-cell Communication Via Exosomesmentioning

confidence: 99%

Exosomes in liver pathology

Sato

Meng²,

Glaser

et al. 2016

Journal of Hepatology

159

145

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Exosomes are small (~100 nm) membrane-bound extracellular vesicles released by various types of cells into biological fluids. They contain proteins, mRNAs and miRNAs as cargo. Different cell types can take up exosomes by endocytosis and the cargo contained within them can be transferred horizontally to these recipient cells. Exosomal proteins and miRNAs can be functional and regulate physiological cell events modifying the microenvironment in target cells, a key event of liver pathology. Exosome-mediated cell-cell communication can alter tumor growth, cell migration, anti-viral infection and hepatocyte regeneration, indicating that exosomes have great potential development as diagnostic or therapeutic tools. Analyses of circulating total or exosomal miRNAs have identified a large number of candidate miRNAs that are regulated in liver diseases, and the diagnostic testing using single or multiple miRNAs shows good sensitivity and specificity. Some candidate miRNAs have been identified to play an important role in various liver disorders. This review summarizes recent findings on the role of extracellular vesicles in liver diseases and their diagnostic and therapeutic potential, mainly focusing on exosomes but also includes microvesicles in liver pathology.

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“…ECs generate a significant percentage of the serum pool of exosomes (32) and are anatomically situated near HSCs, we focused on ECs and their exosome production as a paracrine mechanism of HSC migration (33). First, we performed angiogenesis pathway-specific microarray studies to identify specific candidate EC genes for further study.…”

Section: Sk1 Is An Ec-derived Exosome Protein-becausementioning

confidence: 99%

Exosome Adherence and Internalization by Hepatic Stellate Cells Triggers Sphingosine 1-Phosphate-dependent Migration

Wang

Ding

Yaqoob

et al. 2015

Journal of Biological Chemistry

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184

172

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Exosomes are cell-derived extracellular vesicles thought to promote intercellular communication by delivering specific content to target cells. The aim of this study was to determine whether endothelial cell (EC)-derived exosomes could regulate the phenotype of hepatic stellate cells (HSCs). Initial microarray studies showed that fibroblast growth factor 2 induced a 2.4-fold increase in mRNA levels of sphingosine kinase 1 (SK1). Exosomes derived from an SK1-overexpressing EC line increased HSC migration 3.2-fold. Migration was not conferred by the dominant negative SK1 exosome. Incubation of HSCs with exosomes was also associated with an 8.3-fold increase in phosphorylation of AKT and 2.5-fold increase in migration. Exosomes were found to express the matrix protein and integrin ligand fibronectin (FN) by Western blot analysis and transmission electron microscopy. Blockade of the FN-integrin interaction with a CD29 neutralizing antibody or the RGD peptide attenuated exosome-induced HSC AKT phosphorylation and migration. Inhibition of endocytosis with transfection of dynamin siRNA, the dominant negative dynamin GTPase construct Dyn2K44A, or the pharmacological inhibitor Dynasore significantly attenuated exosome-induced AKT phosphorylation. SK1 levels were increased in serum exosomes derived from mice with experimental liver fibrosis, and SK1 mRNA levels were up-regulated 2.5-fold in human liver cirrhosis patient samples. Finally, S1PR2 inhibition protected mice from CCl 4 -induced liver fibrosis. Therefore, EC-derived SK1-containing exosomes regulate HSC signaling and migration through FNintegrin-dependent exosome adherence and dynamin-dependent exosome internalization. These findings advance our understanding of EC/HSC cross-talk and identify exosomes as a potential target to attenuate pathobiology signals.

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Hepatitis C Virus Infection Induces Autocrine Interferon Signaling by Human Liver Endothelial Cells and Release of Exosomes, Which Inhibits Viral Replication

Cited by 100 publications

References 62 publications

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Exosomes in liver pathology

Exosome Adherence and Internalization by Hepatic Stellate Cells Triggers Sphingosine 1-Phosphate-dependent Migration

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