Hepatitis C Virus-Induced Exosomal MicroRNAs and Toll-Like Receptor 7 Polymorphism Regulate B-Cell Activating Factor

doi:10.1128/mBio.02764-21

中山醫學大學機構典藏 CSMUIR > 中山醫學大學研究成果 > 期刊論文 > Item 310902500/23592

Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/23592

Title:	Hepatitis C Virus-Induced Exosomal MicroRNAs and Toll-Like Receptor 7 Polymorphism Regulate B-Cell Activating Factor
Authors:	Liao, TL;Chen, YM;Hsieh, SL;Tang, KT;Chen, DY;Yang, YY;Liu, HJ;Yang, SS
Keywords:	hepatitis C virus;mixed cryoglobulinemia;exosomal microRNA-122;B-cell activating factor;TLR7
Date:	2021
Issue Date:	2022-08-05T09:39:46Z (UTC)
Publisher:	AMER SOC MICROBIOLOGY
ISSN:	2150-7511
Abstract:	There are large gaps in understanding the molecular machinery accounting for the association of hepatitis C virus (HCV) infection with autoimmunity. Mixed cryoglobulinemia (MC) is the most common HCV-associated extrahepatic manifestation, which is characterized by B-cell lymphoproliferation and autoantibody production. B-cell activating factor (BAFF) is a member of the tumor necrosis factor family and plays an important role in B-cell proliferation. We explored the roles of hepatocyte-derived exosomal microRNAs (exo-miRNAs) and BAFF in the extrahepatic diseases of HCV infection. The exo-miRNA profiles were explored using a next-generation sequencing approach, followed by quantitative reverse transcription-PCR validation. The Toll-like receptor 7 (TLR7) polymorphism were analyzed using quantitative PCR. The biological function of exo-miRNAs and TLR7 polymorphism in BAFF expression was evaluated by using immunoblotting and enzyme-linked immunosorbent assay. Significantly increased levels of BAFF, exosomes, and TLR7 were found in HCV patients, particularly in those with MC (P < 0.005). HCV-infected hepatocyte-derived miR-122/let-7b/miR-206 upregulated BAFF expression in human macrophages through exosome transmission and TLR7 activation. Analysis of a TLR7 single-nucleotide polymorphism (rs3853839) revealed that G-allele carriers had increased TLR7 transcripts, resulting in more BAFF expression induced by hepatocyte-derived exo-miR-122, compared to those in C-allele carriers (P < 0.005). We identified HCV-infected hepatocyte-derived GU-enriched miRNAs (e.g., miR-122/let-7b/miR-206) as a TLR7 ligand that could induce BAFF production in macrophages through exosome transmission. The polymorphism in TLR7 is associated with the BAFF levels induced by exo-miR-122. It may be a potential predisposing factor of MC syndrome development. IMPORTANCE HCV remains an important cause of liver disease worldwide. Accumulating evidence has demonstrated that HCV infection is associated with B cell lymphoproliferative disorders such as MC. Approximately half of the patients infected with HCV develop MC, but the real reason and regulatory mechanism is still uncertain. Here, we demonstrate a novel relationship between HCV-infected hepatocyte-derived exo-miRNAs, host genetic background in TLR7, and BAFF expression. We validate that HCV-induced GU- enriched miRNAs (e.g., miR-122, let-7b, and miR-206) upregulated BAFF expression through exosome transmission and TLR7 activation. This mechanism of miRNAs action is implicated in HCV-infected hepatocyte-immune system communication and is important in extrahepatic manifestation development, thus representing a possible target for HCV infection and extrahepatic diseases treatment. In addition, we show that a functional polymorphism in TLR7 is a potential predisposing factor of MC development. Our results elucidate the molecular machinery in order to better understand the association of HCV infection with autoimmunity.
URI:	http://dx.doi.org/10.1128/mBio.02764-21 https://www.webofscience.com/wos/woscc/full-record/WOS:000744177300001 https://ir.csmu.edu.tw:8080/handle/310902500/23592
Relation:	MBIO ,2021,v12,issue 6
Appears in Collections:	[中山醫學大學研究成果] 期刊論文

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