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Inhibition of Glycolysis Impairs Retinoic Acid-Inducible Gene I–Mediated Antiviral Responses in Primary Human Dendritic Cells

Dendritic cells (DCs) are important mediators of the induction and regulation of adaptive immune responses following microbial infection and inflammation. Sensing environmental danger signals including viruses, microbial products, or inflammatory stimuli by DCs leads to the rapid transition from a r...

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Autores principales: Zevini, Alessandra, Palermo, Enrico, Di Carlo, Daniele, Alexandridi, Magdalini, Rinaldo, Serena, Paone, Alessio, Cutruzzola, Francesca, Etna, Marilena P., Coccia, Eliana M., Olagnier, David, Hiscott, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339606/
https://www.ncbi.nlm.nih.gov/pubmed/35923800
http://dx.doi.org/10.3389/fcimb.2022.910864
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author Zevini, Alessandra
Palermo, Enrico
Di Carlo, Daniele
Alexandridi, Magdalini
Rinaldo, Serena
Paone, Alessio
Cutruzzola, Francesca
Etna, Marilena P.
Coccia, Eliana M.
Olagnier, David
Hiscott, John
author_facet Zevini, Alessandra
Palermo, Enrico
Di Carlo, Daniele
Alexandridi, Magdalini
Rinaldo, Serena
Paone, Alessio
Cutruzzola, Francesca
Etna, Marilena P.
Coccia, Eliana M.
Olagnier, David
Hiscott, John
author_sort Zevini, Alessandra
collection PubMed
description Dendritic cells (DCs) are important mediators of the induction and regulation of adaptive immune responses following microbial infection and inflammation. Sensing environmental danger signals including viruses, microbial products, or inflammatory stimuli by DCs leads to the rapid transition from a resting state to an activated mature state. DC maturation involves enhanced capturing and processing of antigens for presentation by major histocompatibility complex (MHC) class I and class II, upregulation of chemokines and their receptors, cytokines and costimulatory molecules, and migration to lymphoid tissues where they prime naive T cells. Orchestrating a cellular response to environmental threats requires a high bioenergetic cost that accompanies the metabolic reprogramming of DCs during activation. We previously demonstrated that DCs undergo a striking functional transition after stimulation of the retinoic acid-inducible gene I (RIG-I) pathway with a synthetic 5′ triphosphate containing RNA (termed M8), consisting of the upregulation of interferon (IFN)–stimulated antiviral genes, increased DC phagocytosis, activation of a proinflammatory phenotype, and induction of markers associated with immunogenic cell death. In the present study, we set out to determine the metabolic changes associated with RIG-I stimulation by M8. The rate of glycolysis in primary human DCs was increased in response to RIG-I activation, and glycolytic reprogramming was an essential requirement for DC activation. Pharmacological inhibition of glycolysis in monocyte-derived dendritic cells (MoDCs) impaired type I IFN induction and signaling by disrupting the TBK1-IRF3-STAT1 axis, thereby countering the antiviral activity induced by M8. Functionally, the impaired IFN response resulted in enhanced viral replication of dengue, coronavirus 229E, and Coxsackie B5.
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spelling pubmed-93396062022-08-02 Inhibition of Glycolysis Impairs Retinoic Acid-Inducible Gene I–Mediated Antiviral Responses in Primary Human Dendritic Cells Zevini, Alessandra Palermo, Enrico Di Carlo, Daniele Alexandridi, Magdalini Rinaldo, Serena Paone, Alessio Cutruzzola, Francesca Etna, Marilena P. Coccia, Eliana M. Olagnier, David Hiscott, John Front Cell Infect Microbiol Cellular and Infection Microbiology Dendritic cells (DCs) are important mediators of the induction and regulation of adaptive immune responses following microbial infection and inflammation. Sensing environmental danger signals including viruses, microbial products, or inflammatory stimuli by DCs leads to the rapid transition from a resting state to an activated mature state. DC maturation involves enhanced capturing and processing of antigens for presentation by major histocompatibility complex (MHC) class I and class II, upregulation of chemokines and their receptors, cytokines and costimulatory molecules, and migration to lymphoid tissues where they prime naive T cells. Orchestrating a cellular response to environmental threats requires a high bioenergetic cost that accompanies the metabolic reprogramming of DCs during activation. We previously demonstrated that DCs undergo a striking functional transition after stimulation of the retinoic acid-inducible gene I (RIG-I) pathway with a synthetic 5′ triphosphate containing RNA (termed M8), consisting of the upregulation of interferon (IFN)–stimulated antiviral genes, increased DC phagocytosis, activation of a proinflammatory phenotype, and induction of markers associated with immunogenic cell death. In the present study, we set out to determine the metabolic changes associated with RIG-I stimulation by M8. The rate of glycolysis in primary human DCs was increased in response to RIG-I activation, and glycolytic reprogramming was an essential requirement for DC activation. Pharmacological inhibition of glycolysis in monocyte-derived dendritic cells (MoDCs) impaired type I IFN induction and signaling by disrupting the TBK1-IRF3-STAT1 axis, thereby countering the antiviral activity induced by M8. Functionally, the impaired IFN response resulted in enhanced viral replication of dengue, coronavirus 229E, and Coxsackie B5. Frontiers Media S.A. 2022-07-18 /pmc/articles/PMC9339606/ /pubmed/35923800 http://dx.doi.org/10.3389/fcimb.2022.910864 Text en Copyright © 2022 Zevini, Palermo, Di Carlo, Alexandridi, Rinaldo, Paone, Cutruzzola, Etna, Coccia, Olagnier and Hiscott https://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) and the copyright owner(s) 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 Cellular and Infection Microbiology
Zevini, Alessandra
Palermo, Enrico
Di Carlo, Daniele
Alexandridi, Magdalini
Rinaldo, Serena
Paone, Alessio
Cutruzzola, Francesca
Etna, Marilena P.
Coccia, Eliana M.
Olagnier, David
Hiscott, John
Inhibition of Glycolysis Impairs Retinoic Acid-Inducible Gene I–Mediated Antiviral Responses in Primary Human Dendritic Cells
title Inhibition of Glycolysis Impairs Retinoic Acid-Inducible Gene I–Mediated Antiviral Responses in Primary Human Dendritic Cells
title_full Inhibition of Glycolysis Impairs Retinoic Acid-Inducible Gene I–Mediated Antiviral Responses in Primary Human Dendritic Cells
title_fullStr Inhibition of Glycolysis Impairs Retinoic Acid-Inducible Gene I–Mediated Antiviral Responses in Primary Human Dendritic Cells
title_full_unstemmed Inhibition of Glycolysis Impairs Retinoic Acid-Inducible Gene I–Mediated Antiviral Responses in Primary Human Dendritic Cells
title_short Inhibition of Glycolysis Impairs Retinoic Acid-Inducible Gene I–Mediated Antiviral Responses in Primary Human Dendritic Cells
title_sort inhibition of glycolysis impairs retinoic acid-inducible gene i–mediated antiviral responses in primary human dendritic cells
topic Cellular and Infection Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339606/
https://www.ncbi.nlm.nih.gov/pubmed/35923800
http://dx.doi.org/10.3389/fcimb.2022.910864
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