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Review
. 2024 Nov 17;16(11):1785.
doi: 10.3390/v16111785.

Extracellular Vesicles in Viral Liver Diseases

Affiliations
Review

Extracellular Vesicles in Viral Liver Diseases

Elias Kouroumalis et al. Viruses. .

Abstract

Extracellular vesicles (EVs) are bilayer vesicles released by cells in the microenvironment of the liver including parenchymal and non-parenchymal cells. They are the third important mechanism in the communications between cells, besides the secretion of cytokines and chemokines and the direct cell-to-cell contact. The aim of this review is to discuss the important role of EVs in viral liver disease, as there is increasing evidence that the transportation of viral proteins, all types of RNA, and viral particles including complete virions is implicated in the pathogenesis of both viral cirrhosis and viral-related hepatocellular carcinoma. The biogenesis of EVs is discussed and their role in the pathogenesis of viral liver diseases is presented. Their use as diagnostic and prognostic biomarkers is also analyzed. Most importantly, the significance of possible novel treatment strategies for liver fibrosis and hepatocellular carcinoma is presented, although available data are based on experimental evidence and clinical trials have not been reported.

Keywords: exosomes; extracellular vesicles; hepatitis B; hepatitis C; hepatocellular carcinoma; liver fibrosis; miRNAs.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
A simplified diagram indicating the roles of exosomes in viral hepatitis. HBV and HCV multiplied within the infected hepatocytes spread viral RNAs and miRNAs through exosomes to adjacent hepatocytes inducing further viral replication. At the same time, viral exosomes inhibit the defensive immune responses launched by immune cells against viruses. HCV-derived exosomes inhibit TLR3 of the hepatocytes reducing the expression of ISGs. In addition, exosomes from HBV lead to exhaustion of the T effector cells by upregulating PD-L1 expression in the surface of monocytes. On the other hand, HBV-miR-3 exosomes from HBV-infected hepatocytes activate NK cells to produce IFNa through upregulation of the NKGD protein in macrophages. Moreover, exosomes produced by either infected hepatocytes or viruses activate qHSCs into aHSCs. EVs produced by qHSCs are rich in miR-214, Twist 1, which attenuates the profibrotic function of activated HSCs, while exosomes from aHSCs contain CTGF and proteins that activate myofibroblasts to produce ECM or activate qHSCs. For more details, see text. MØ: macrophages; ISG: immune responsive genes; MF: myofibroblasts; DC: dendritic cells. Black arrows indicate activation. Red arrows indicate inhibition.
Figure 2
Figure 2
Mechanisms of exosome interference in HCC. HCC-derived exosomes promote proliferation, migration, and invasion of other HCC cells, either directly or indirectly through angiogenesis by activating LSECs to produce exosomes rich in angiogenetic factors. They also promote both stellate cell activation and inhibition of macrophages and NK cells to evade immune response. On the other hand, HCC-derived exosomes may activate dendritic cells to promote the immune response against HCC. For details see text. CTL: Cytotoxic T lymphocytes. DC: dendritic cells. Black arrows indicate activation. Red arrows indicate inhibition.

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