Cargando…
Extracellular Vesicles Including Exosomes Regulate Innate Immune Responses to Hepatitis B Virus Infection
The innate immune system is essential for controlling viral infection. Hepatitis B virus (HBV) persistently infects human hepatocytes and causes hepatocellular carcinoma. However, the innate immune response to HBV infection in vivo remains unclear. Using a tree shrew animal model, we showed that HBV...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005343/ https://www.ncbi.nlm.nih.gov/pubmed/27630638 http://dx.doi.org/10.3389/fimmu.2016.00335 |
_version_ | 1782450906227277824 |
---|---|
author | Kouwaki, Takahisa Fukushima, Yoshimi Daito, Takuji Sanada, Takahiro Yamamoto, Naoki Mifsud, Edin J. Leong, Chean Ring Tsukiyama-Kohara, Kyoko Kohara, Michinori Matsumoto, Misako Seya, Tsukasa Oshiumi, Hiroyuki |
author_facet | Kouwaki, Takahisa Fukushima, Yoshimi Daito, Takuji Sanada, Takahiro Yamamoto, Naoki Mifsud, Edin J. Leong, Chean Ring Tsukiyama-Kohara, Kyoko Kohara, Michinori Matsumoto, Misako Seya, Tsukasa Oshiumi, Hiroyuki |
author_sort | Kouwaki, Takahisa |
collection | PubMed |
description | The innate immune system is essential for controlling viral infection. Hepatitis B virus (HBV) persistently infects human hepatocytes and causes hepatocellular carcinoma. However, the innate immune response to HBV infection in vivo remains unclear. Using a tree shrew animal model, we showed that HBV infection induced hepatic interferon (IFN)-γ expression during early infection. Our in vitro study demonstrated that hepatic NK cells produced IFN-γ in response to HBV only in the presence of hepatic F4/80(+) cells. Moreover, extracellular vesicles (EVs) released from HBV-infected hepatocytes contained viral nucleic acids and induced NKG2D ligand expression in macrophages by stimulating MyD88, TICAM-1, and MAVS-dependent pathways. In addition, depletion of exosomes from EVs markedly reduced NKG2D ligand expression, suggesting the importance of exosomes for NK cell activation. In contrast, infection of hepatocytes with HBV increased immunoregulatory microRNA levels in EVs and exosomes, which were transferred to macrophages, thereby suppressing IL-12p35 mRNA expression in macrophages to counteract the host innate immune response. IFN-γ increased the hepatic expression of DDX60 and augmented the DDX60-dependent degradation of cytoplasmic HBV RNA. Our results elucidated the crucial role of exosomes in antiviral innate immune response against HBV. ACCESSION NUMBER: Accession number of RNA-seq data is DRA004164 (DRA in DDBJ). |
format | Online Article Text |
id | pubmed-5005343 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-50053432016-09-14 Extracellular Vesicles Including Exosomes Regulate Innate Immune Responses to Hepatitis B Virus Infection Kouwaki, Takahisa Fukushima, Yoshimi Daito, Takuji Sanada, Takahiro Yamamoto, Naoki Mifsud, Edin J. Leong, Chean Ring Tsukiyama-Kohara, Kyoko Kohara, Michinori Matsumoto, Misako Seya, Tsukasa Oshiumi, Hiroyuki Front Immunol Immunology The innate immune system is essential for controlling viral infection. Hepatitis B virus (HBV) persistently infects human hepatocytes and causes hepatocellular carcinoma. However, the innate immune response to HBV infection in vivo remains unclear. Using a tree shrew animal model, we showed that HBV infection induced hepatic interferon (IFN)-γ expression during early infection. Our in vitro study demonstrated that hepatic NK cells produced IFN-γ in response to HBV only in the presence of hepatic F4/80(+) cells. Moreover, extracellular vesicles (EVs) released from HBV-infected hepatocytes contained viral nucleic acids and induced NKG2D ligand expression in macrophages by stimulating MyD88, TICAM-1, and MAVS-dependent pathways. In addition, depletion of exosomes from EVs markedly reduced NKG2D ligand expression, suggesting the importance of exosomes for NK cell activation. In contrast, infection of hepatocytes with HBV increased immunoregulatory microRNA levels in EVs and exosomes, which were transferred to macrophages, thereby suppressing IL-12p35 mRNA expression in macrophages to counteract the host innate immune response. IFN-γ increased the hepatic expression of DDX60 and augmented the DDX60-dependent degradation of cytoplasmic HBV RNA. Our results elucidated the crucial role of exosomes in antiviral innate immune response against HBV. ACCESSION NUMBER: Accession number of RNA-seq data is DRA004164 (DRA in DDBJ). Frontiers Media S.A. 2016-08-31 /pmc/articles/PMC5005343/ /pubmed/27630638 http://dx.doi.org/10.3389/fimmu.2016.00335 Text en Copyright © 2016 Kouwaki, Fukushima, Daito, Sanada, Yamamoto, Mifsud, Leong, Tsukiyama-Kohara, Kohara, Matsumoto, Seya and Oshiumi. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Kouwaki, Takahisa Fukushima, Yoshimi Daito, Takuji Sanada, Takahiro Yamamoto, Naoki Mifsud, Edin J. Leong, Chean Ring Tsukiyama-Kohara, Kyoko Kohara, Michinori Matsumoto, Misako Seya, Tsukasa Oshiumi, Hiroyuki Extracellular Vesicles Including Exosomes Regulate Innate Immune Responses to Hepatitis B Virus Infection |
title | Extracellular Vesicles Including Exosomes Regulate Innate Immune Responses to Hepatitis B Virus Infection |
title_full | Extracellular Vesicles Including Exosomes Regulate Innate Immune Responses to Hepatitis B Virus Infection |
title_fullStr | Extracellular Vesicles Including Exosomes Regulate Innate Immune Responses to Hepatitis B Virus Infection |
title_full_unstemmed | Extracellular Vesicles Including Exosomes Regulate Innate Immune Responses to Hepatitis B Virus Infection |
title_short | Extracellular Vesicles Including Exosomes Regulate Innate Immune Responses to Hepatitis B Virus Infection |
title_sort | extracellular vesicles including exosomes regulate innate immune responses to hepatitis b virus infection |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005343/ https://www.ncbi.nlm.nih.gov/pubmed/27630638 http://dx.doi.org/10.3389/fimmu.2016.00335 |
work_keys_str_mv | AT kouwakitakahisa extracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisbvirusinfection AT fukushimayoshimi extracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisbvirusinfection AT daitotakuji extracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisbvirusinfection AT sanadatakahiro extracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisbvirusinfection AT yamamotonaoki extracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisbvirusinfection AT mifsudedinj extracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisbvirusinfection AT leongcheanring extracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisbvirusinfection AT tsukiyamakoharakyoko extracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisbvirusinfection AT koharamichinori extracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisbvirusinfection AT matsumotomisako extracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisbvirusinfection AT seyatsukasa extracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisbvirusinfection AT oshiumihiroyuki extracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisbvirusinfection |