Circulating and exosome-packaged hepatitis c single-stranded RNA induce monocyte differentiation via tlr7/8 to polarized macrophages and fibrocytes

Banishree Saha, Karen Kodys, Adeyinka Adejumo, G. Szabó

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Monocytes and macrophages (MFs) play a central role in the pathogenesis of chronic hepatitis C virus (HCV) infection. The tissue microenvironment triggers monocyte differentiation into MFs, with polarization ranging within the spectrum of M1 (classical) to M2 (alternative) activation. Recently, we demonstrated that HCV infection leads to monocyte differentiation into polarized MFs that mediate stellate cell activation via TGF-b. In this study, we aimed to identify the viral factor(s) that mediate monocyte-to-MF differentiation. We performed coculture experiments using healthy monocytes with exosome-packaged HCV, cell-free HCV, or HCV ssRNA. Coculture of monocytes with exosome-packaged HCV, cell-free HCV, or HCV ssRNA induced differentiation into MFs with high M2 surface marker expression and production of pro-and anti-inflammatory cytokines. The HCV ssRNA-induced monocyte activation and differentiation into MFs could be prevented by TLR7 or TLR8 knockdown. Furthermore, TLR7 or TLR8 stimulation, independent of HCV, caused monocyte differentiation and M2 MF polarization. In vivo, in chronic HCV-infected patients, we found increased expression of TLR7/8 in circulating monocytes that was associated with increased intracellular expression of procollagen. Furthermore, knockdown of TLR8 completely attenuated collagen expression in monocytes exposed to HCV, and knockdown of TLR7 partially attenuated this expression, suggesting roles for TLR7/8 in induction of fibrocytes in HCV infection. We identified TLR7/8 as mediators of monocyte differentiation and M2 MF polarization during HCV infection. Further, we demonstrated that HCV ssRNA and other TLR7/8 ligands promote MF polarization and generation of circulating fibrocytes.

Original languageEnglish
Pages (from-to)1974-1984
Number of pages11
JournalJournal of Immunology
Volume198
Issue number5
DOIs
Publication statusPublished - Mar 1 2017

Fingerprint

Exosomes
Hepacivirus
Hepatitis
Monocytes
Macrophages
RNA
Virus Diseases
Chronic Hepatitis C
Coculture Techniques
Procollagen

ASJC Scopus subject areas

  • Immunology

Cite this

Circulating and exosome-packaged hepatitis c single-stranded RNA induce monocyte differentiation via tlr7/8 to polarized macrophages and fibrocytes. / Saha, Banishree; Kodys, Karen; Adejumo, Adeyinka; Szabó, G.

In: Journal of Immunology, Vol. 198, No. 5, 01.03.2017, p. 1974-1984.

Research output: Contribution to journalArticle

@article{1869870d73124efa872dd6986290eebd,
title = "Circulating and exosome-packaged hepatitis c single-stranded RNA induce monocyte differentiation via tlr7/8 to polarized macrophages and fibrocytes",
abstract = "Monocytes and macrophages (MFs) play a central role in the pathogenesis of chronic hepatitis C virus (HCV) infection. The tissue microenvironment triggers monocyte differentiation into MFs, with polarization ranging within the spectrum of M1 (classical) to M2 (alternative) activation. Recently, we demonstrated that HCV infection leads to monocyte differentiation into polarized MFs that mediate stellate cell activation via TGF-b. In this study, we aimed to identify the viral factor(s) that mediate monocyte-to-MF differentiation. We performed coculture experiments using healthy monocytes with exosome-packaged HCV, cell-free HCV, or HCV ssRNA. Coculture of monocytes with exosome-packaged HCV, cell-free HCV, or HCV ssRNA induced differentiation into MFs with high M2 surface marker expression and production of pro-and anti-inflammatory cytokines. The HCV ssRNA-induced monocyte activation and differentiation into MFs could be prevented by TLR7 or TLR8 knockdown. Furthermore, TLR7 or TLR8 stimulation, independent of HCV, caused monocyte differentiation and M2 MF polarization. In vivo, in chronic HCV-infected patients, we found increased expression of TLR7/8 in circulating monocytes that was associated with increased intracellular expression of procollagen. Furthermore, knockdown of TLR8 completely attenuated collagen expression in monocytes exposed to HCV, and knockdown of TLR7 partially attenuated this expression, suggesting roles for TLR7/8 in induction of fibrocytes in HCV infection. We identified TLR7/8 as mediators of monocyte differentiation and M2 MF polarization during HCV infection. Further, we demonstrated that HCV ssRNA and other TLR7/8 ligands promote MF polarization and generation of circulating fibrocytes.",
author = "Banishree Saha and Karen Kodys and Adeyinka Adejumo and G. Szab{\'o}",
year = "2017",
month = "3",
day = "1",
doi = "10.4049/jimmunol.1600797",
language = "English",
volume = "198",
pages = "1974--1984",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "5",

}

TY - JOUR

T1 - Circulating and exosome-packaged hepatitis c single-stranded RNA induce monocyte differentiation via tlr7/8 to polarized macrophages and fibrocytes

AU - Saha, Banishree

AU - Kodys, Karen

AU - Adejumo, Adeyinka

AU - Szabó, G.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Monocytes and macrophages (MFs) play a central role in the pathogenesis of chronic hepatitis C virus (HCV) infection. The tissue microenvironment triggers monocyte differentiation into MFs, with polarization ranging within the spectrum of M1 (classical) to M2 (alternative) activation. Recently, we demonstrated that HCV infection leads to monocyte differentiation into polarized MFs that mediate stellate cell activation via TGF-b. In this study, we aimed to identify the viral factor(s) that mediate monocyte-to-MF differentiation. We performed coculture experiments using healthy monocytes with exosome-packaged HCV, cell-free HCV, or HCV ssRNA. Coculture of monocytes with exosome-packaged HCV, cell-free HCV, or HCV ssRNA induced differentiation into MFs with high M2 surface marker expression and production of pro-and anti-inflammatory cytokines. The HCV ssRNA-induced monocyte activation and differentiation into MFs could be prevented by TLR7 or TLR8 knockdown. Furthermore, TLR7 or TLR8 stimulation, independent of HCV, caused monocyte differentiation and M2 MF polarization. In vivo, in chronic HCV-infected patients, we found increased expression of TLR7/8 in circulating monocytes that was associated with increased intracellular expression of procollagen. Furthermore, knockdown of TLR8 completely attenuated collagen expression in monocytes exposed to HCV, and knockdown of TLR7 partially attenuated this expression, suggesting roles for TLR7/8 in induction of fibrocytes in HCV infection. We identified TLR7/8 as mediators of monocyte differentiation and M2 MF polarization during HCV infection. Further, we demonstrated that HCV ssRNA and other TLR7/8 ligands promote MF polarization and generation of circulating fibrocytes.

AB - Monocytes and macrophages (MFs) play a central role in the pathogenesis of chronic hepatitis C virus (HCV) infection. The tissue microenvironment triggers monocyte differentiation into MFs, with polarization ranging within the spectrum of M1 (classical) to M2 (alternative) activation. Recently, we demonstrated that HCV infection leads to monocyte differentiation into polarized MFs that mediate stellate cell activation via TGF-b. In this study, we aimed to identify the viral factor(s) that mediate monocyte-to-MF differentiation. We performed coculture experiments using healthy monocytes with exosome-packaged HCV, cell-free HCV, or HCV ssRNA. Coculture of monocytes with exosome-packaged HCV, cell-free HCV, or HCV ssRNA induced differentiation into MFs with high M2 surface marker expression and production of pro-and anti-inflammatory cytokines. The HCV ssRNA-induced monocyte activation and differentiation into MFs could be prevented by TLR7 or TLR8 knockdown. Furthermore, TLR7 or TLR8 stimulation, independent of HCV, caused monocyte differentiation and M2 MF polarization. In vivo, in chronic HCV-infected patients, we found increased expression of TLR7/8 in circulating monocytes that was associated with increased intracellular expression of procollagen. Furthermore, knockdown of TLR8 completely attenuated collagen expression in monocytes exposed to HCV, and knockdown of TLR7 partially attenuated this expression, suggesting roles for TLR7/8 in induction of fibrocytes in HCV infection. We identified TLR7/8 as mediators of monocyte differentiation and M2 MF polarization during HCV infection. Further, we demonstrated that HCV ssRNA and other TLR7/8 ligands promote MF polarization and generation of circulating fibrocytes.

UR - http://www.scopus.com/inward/record.url?scp=85014940202&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85014940202&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1600797

DO - 10.4049/jimmunol.1600797

M3 - Article

C2 - 28122964

AN - SCOPUS:85014940202

VL - 198

SP - 1974

EP - 1984

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 5

ER -