Expression and functionality of Toll- and RIG-like receptors in HepaRG cells

Luangsay, Souphalone; Ait-Goughoulte, Malika; Michelet, Maud; Floriot, Océane; Bonnin, Marc; Gruffaz, Marion; Rivoire, Michel; Fletcher, Simon P.; Javanbakht, Hassan; Lucifora, Julie; Zoulim, Fabien; Durantel, David

doi:10.1016/j.jhep.2015.06.022

Cited by 60 publications

(78 citation statements)

References 38 publications

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“…To investigate the mechanisms of induction of inflammatory signaling by HCV proteins, we used HepaRG cells, which are human hepatocyte progenitors closely related to primary cells, notably with respect to their fully functional immune signaling network (32,45,46). Since we have previously shown that the viral polymerase triggers inflammatory signaling in hepatocytes (12), we now analyzed its effects on the level of expression of several cellular PRRs (i.e., RIG-I, MDA5, TLR3, TLR9, NOD1, and NOD2).…”

Section: Ns5b Increases Nod1 Expression and Activates Its Downstream mentioning

confidence: 99%

NOD1 Participates in the Innate Immune Response Triggered by Hepatitis C Virus Polymerase

Vegna

Grégoire

Moreau

et al. 2016

J Virol

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Hepatitis C virus (HCV) triggers innate immunity signaling in the infected cell. Replication of the viral genome is dispensable for this phenotype, and we along with others have recently shown that NS5B, the viral RNA-dependent RNA polymerase, synthesizes double-stranded RNA (dsRNA) from cellular templates, thus eliciting an inflammatory response, notably via activation of type I interferon and lymphotoxin ␤. Here, we investigated intracellular signal transduction pathways involved in this process. Using HepaRG cells, a model that largely recapitulates the in vivo complexities of the innate immunity receptor signaling, we have confirmed that NS5B triggered increased expression of the canonical pattern recognition receptors (PRRs) specific for dsRNA, namely, RIG-I, MDA5, and Toll-like receptor 3 (TLR3). Unexpectedly, intracellular dsRNA also led to accumulation of NOD1, a receptor classically involved in recognition of bacterial peptidoglycans. NOD1 activation, confirmed by analysis of its downstream targets, was likely due to its interaction with dsRNA and was independent of RIG-I and mitochondrial antiviral signaling protein (MAVS/IPS-1/Cardif/VISA) signaling. It is likely to have a functional significance in the cellular response in the context of HCV infection since interference with the NOD1 pathway severely reduced the inflammatory response elicited by NS5B. IMPORTANCEIn this study, we show that NOD1, a PRR that normally senses bacterial peptidoglycans, is activated by HCV viral polymerase, probably through an interaction with dsRNA, suggesting that NOD1 acts as an RNA ligand recognition receptor. In consequence, interference with NOD1-mediated signaling significantly weakens the inflammatory response to dsRNA. These results add a new level of complexity to the understanding of the cross talk between different classes of pattern recognition receptors and may be related to certain complications of chronic hepatitis C virus infection.

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Section: Ns5b Increases Nod1 Expression and Activates Its Downstream mentioning

confidence: 99%

NOD1 Participates in the Innate Immune Response Triggered by Hepatitis C Virus Polymerase

Vegna

Grégoire

Moreau

et al. 2016

J Virol

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“…Initial studies demonstrated that these chemokines were mainly produced after an adaptive immune response (11)(12)(13). However, more recent studies have shown that HBV can also stimulate production of chemokines such as CXCL10 at early time points (14)(15)(16). Unfortunately, antiviral innate immunity against HBV that occurs minutes after virus contact is an area that has been neglected and necessitates further investigation.…”

mentioning

confidence: 99%

Hepatitis B Virus and DNA Stimulation Trigger a Rapid Innate Immune Response through NF-κB

Yoneda

Hyun

Jakubski

et al. 2016

The Journal of Immunology

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Cell-intrinsic innate immunity provides a rapid first line of defense to thwart invading viral pathogens through the production of antiviral and inflammatory genes. However, the presence of many of these signaling pathways in the liver and their role in hepatitis B virus (HBV) pathogenesis is unknown. Recent identification of intracellular DNA-sensing pathways and involvement in numerous diverse disease processes including viral pathogenesis and carcinogenesis suggest a role for these processes in HBV infection. To characterize HBV-intrinsic innate immune responses and the role of DNA- and RNA-sensing pathways in the liver, we used in vivo and in vitro models including analysis of gene expression in liver biopsies from HBV-infected patients. In addition, mRNA and protein expression were measured in HBV-stimulated and DNA-treated hepatoma cell lines and primary human hepatocytes. In this article, we report that HBV and foreign DNA stimulation results in innate immune responses characterized by the production of inflammatory chemokines in hepatocytes. Analysis of liver biopsies from HBV-infected patients supported a correlation among hepatic expression of specific chemokines. In addition, HBV elicits a much broader range of gene expression alterations. The induction of chemokines, including CXCL10, is mediated by melanoma differentiation–associated gene 5 and NF-κB–dependent pathways after HBV stimulation. In conclusion, HBV-stimulated pathways predominantly activate an inflammatory response that would promote the development of hepatitis. Understanding the mechanism underlying these virus–host interactions may provide new strategies to trigger noncytopathic clearance of covalently closed circular DNA to ultimately cure patients with HBV infection.

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“…The analysis of the implication of ISGs in an anti-HBV phenotype in vitro is rendered difficult by the fact that IFN-is a not a very potent inhibitor of HBV replication in relevant cell culture models, including primary human hepatocytes (PHH) and the HepaRG cell line. Those models are relevant because there are functional for innate functions in contrast to hepatoma cells (Luangsay et al, 2015). In our hands, only a 50% reduction of the intracellular total HBV DNA accumulation is observed with a single Mao et al, 2013;Nguyen et al, 2007), following experiments in transfection, have yet to be confirmed.…”

Section: Modes Of Action Of Ifn-mentioning

confidence: 64%

Immune-modulators to combat hepatitis B virus infection: From IFN-α to novel investigational immunotherapeutic strategies

et al. 2015

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Chronic hepatitis B virus (HBV) infection remains a major challenge for clinicians, as there are only two types of approved therapies: interferon-alpha (IFN-α) or its pegylated form, Peg-IFN-α and nucleoside analogs (e.g. tenofovir, entecavir...). The first are used as finite-duration treatments of around 48-52 weeks, while the second must be taken life-long to prevent rebound. Other immune-modulators, including other types of recombinant IFNs and cytokines/chemokines, could be developed for treating chronic hepatitis B. Alternatively, strategies aimed either at restoring or favoring the endogenous production of IFNs, cytokines and/or chemokines, or at alleviating HBV-mediated inhibitory processes could also be envisaged. In this article, we review current investigational, preclinical and clinical efforts to implement immune-modulatory components in the therapy of chronic hepatitis B. This review forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B".

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Expression and functionality of Toll- and RIG-like receptors in HepaRG cells

Abstract: Our results indicate that HepaRG cells express a similar pattern of functional TLR/RLR as compared to PHH, thus qualifying HepaRG cells as a surrogate model to study pathogen interactions within a hepatocyte innate system.

Cited by 60 publications

References 38 publications

NOD1 Participates in the Innate Immune Response Triggered by Hepatitis C Virus Polymerase

NOD1 Participates in the Innate Immune Response Triggered by Hepatitis C Virus Polymerase

Hepatitis B Virus and DNA Stimulation Trigger a Rapid Innate Immune Response through NF-κB

Immune-modulators to combat hepatitis B virus infection: From IFN-α to novel investigational immunotherapeutic strategies

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