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The C-Type Lectin Receptor DC-SIGN Has an Anti-Inflammatory Role in Human M(IL-4) Macrophages in Response to Mycobacterium tuberculosis
DC-SIGN (CD209/CLEC4L) is a C-type lectin receptor (CLR) that serves as a reliable cell-surface marker of interleukin 4 (IL-4)-activated human macrophages [M(IL-4)], which historically represent the most studied subset within the M2 spectrum of macrophage activation. Although DC-SIGN plays important...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006465/ https://www.ncbi.nlm.nih.gov/pubmed/29946317 http://dx.doi.org/10.3389/fimmu.2018.01123 |
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author | Lugo-Villarino, Geanncarlo Troegeler, Anthony Balboa, Luciana Lastrucci, Claire Duval, Carine Mercier, Ingrid Bénard, Alan Capilla, Florence Al Saati, Talal Poincloux, Renaud Kondova, Ivanela Verreck, Frank A. W. Cougoule, Céline Maridonneau-Parini, Isabelle Sasiain, Maria del Carmen Neyrolles, Olivier |
author_facet | Lugo-Villarino, Geanncarlo Troegeler, Anthony Balboa, Luciana Lastrucci, Claire Duval, Carine Mercier, Ingrid Bénard, Alan Capilla, Florence Al Saati, Talal Poincloux, Renaud Kondova, Ivanela Verreck, Frank A. W. Cougoule, Céline Maridonneau-Parini, Isabelle Sasiain, Maria del Carmen Neyrolles, Olivier |
author_sort | Lugo-Villarino, Geanncarlo |
collection | PubMed |
description | DC-SIGN (CD209/CLEC4L) is a C-type lectin receptor (CLR) that serves as a reliable cell-surface marker of interleukin 4 (IL-4)-activated human macrophages [M(IL-4)], which historically represent the most studied subset within the M2 spectrum of macrophage activation. Although DC-SIGN plays important roles in Mycobacterium tuberculosis (Mtb) interactions with dendritic cells, its contribution to the Mtb–macrophage interaction remains poorly understood. Since high levels of IL-4 are correlated with tuberculosis (TB) susceptibility and progression, we investigated the role of DC-SIGN in M(IL-4) macrophages in the TB context. First, we demonstrate that DC-SIGN expression is present both in CD68(+) macrophages found in tuberculous pulmonary lesions of non-human primates, and in the CD14(+) cell population isolated from pleural effusions obtained from TB patients (TB-PE). Likewise, we show that DC-SIGN expression is accentuated in M(IL-4) macrophages derived from peripheral blood CD14(+) monocytes isolated from TB patients, or in macrophages stimulated with acellular TB-PE, arguing for the pertinence of DC-SIGN-expressing macrophages in TB. Second, using a siRNA-mediated gene silencing approach, we performed a transcriptomic analysis of DC-SIGN-depleted M(IL-4) macrophages and revealed the upregulation of pro-inflammatory signals in response to challenge with Mtb, as compared to control cells. This pro-inflammatory gene signature was confirmed by RT-qPCR, cytokine/chemokine-based protein array, and ELISA analyses. We also found that inactivation of DC-SIGN renders M(IL-4) macrophages less permissive to Mtb intracellular growth compared to control cells, despite the equal level of bacteria uptake. Last, at the molecular level, we show that DC-SIGN interferes negatively with the pro-inflammatory response and control of Mtb intracellular growth mediated by another CLR, Dectin-1 (CLEC7A). Collectively, this study highlights a dual role for DC-SIGN as, on the one hand, being a host factor granting advantage for Mtb to parasitize macrophages and, on the other hand, representing a molecular switch to turn off the pro-inflammatory response in these cells to prevent potential immunopathology associated to TB. |
format | Online Article Text |
id | pubmed-6006465 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-60064652018-06-26 The C-Type Lectin Receptor DC-SIGN Has an Anti-Inflammatory Role in Human M(IL-4) Macrophages in Response to Mycobacterium tuberculosis Lugo-Villarino, Geanncarlo Troegeler, Anthony Balboa, Luciana Lastrucci, Claire Duval, Carine Mercier, Ingrid Bénard, Alan Capilla, Florence Al Saati, Talal Poincloux, Renaud Kondova, Ivanela Verreck, Frank A. W. Cougoule, Céline Maridonneau-Parini, Isabelle Sasiain, Maria del Carmen Neyrolles, Olivier Front Immunol Immunology DC-SIGN (CD209/CLEC4L) is a C-type lectin receptor (CLR) that serves as a reliable cell-surface marker of interleukin 4 (IL-4)-activated human macrophages [M(IL-4)], which historically represent the most studied subset within the M2 spectrum of macrophage activation. Although DC-SIGN plays important roles in Mycobacterium tuberculosis (Mtb) interactions with dendritic cells, its contribution to the Mtb–macrophage interaction remains poorly understood. Since high levels of IL-4 are correlated with tuberculosis (TB) susceptibility and progression, we investigated the role of DC-SIGN in M(IL-4) macrophages in the TB context. First, we demonstrate that DC-SIGN expression is present both in CD68(+) macrophages found in tuberculous pulmonary lesions of non-human primates, and in the CD14(+) cell population isolated from pleural effusions obtained from TB patients (TB-PE). Likewise, we show that DC-SIGN expression is accentuated in M(IL-4) macrophages derived from peripheral blood CD14(+) monocytes isolated from TB patients, or in macrophages stimulated with acellular TB-PE, arguing for the pertinence of DC-SIGN-expressing macrophages in TB. Second, using a siRNA-mediated gene silencing approach, we performed a transcriptomic analysis of DC-SIGN-depleted M(IL-4) macrophages and revealed the upregulation of pro-inflammatory signals in response to challenge with Mtb, as compared to control cells. This pro-inflammatory gene signature was confirmed by RT-qPCR, cytokine/chemokine-based protein array, and ELISA analyses. We also found that inactivation of DC-SIGN renders M(IL-4) macrophages less permissive to Mtb intracellular growth compared to control cells, despite the equal level of bacteria uptake. Last, at the molecular level, we show that DC-SIGN interferes negatively with the pro-inflammatory response and control of Mtb intracellular growth mediated by another CLR, Dectin-1 (CLEC7A). Collectively, this study highlights a dual role for DC-SIGN as, on the one hand, being a host factor granting advantage for Mtb to parasitize macrophages and, on the other hand, representing a molecular switch to turn off the pro-inflammatory response in these cells to prevent potential immunopathology associated to TB. Frontiers Media S.A. 2018-06-12 /pmc/articles/PMC6006465/ /pubmed/29946317 http://dx.doi.org/10.3389/fimmu.2018.01123 Text en Copyright © 2018 Lugo-Villarino, Troegeler, Balboa, Lastrucci, Duval, Mercier, Bénard, Capilla, Al Saati, Poincloux, Kondova, Verreck, Cougoule, Maridonneau-Parini, Sasiain and Neyrolles. 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 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 Lugo-Villarino, Geanncarlo Troegeler, Anthony Balboa, Luciana Lastrucci, Claire Duval, Carine Mercier, Ingrid Bénard, Alan Capilla, Florence Al Saati, Talal Poincloux, Renaud Kondova, Ivanela Verreck, Frank A. W. Cougoule, Céline Maridonneau-Parini, Isabelle Sasiain, Maria del Carmen Neyrolles, Olivier The C-Type Lectin Receptor DC-SIGN Has an Anti-Inflammatory Role in Human M(IL-4) Macrophages in Response to Mycobacterium tuberculosis |
title | The C-Type Lectin Receptor DC-SIGN Has an Anti-Inflammatory Role in Human M(IL-4) Macrophages in Response to Mycobacterium tuberculosis |
title_full | The C-Type Lectin Receptor DC-SIGN Has an Anti-Inflammatory Role in Human M(IL-4) Macrophages in Response to Mycobacterium tuberculosis |
title_fullStr | The C-Type Lectin Receptor DC-SIGN Has an Anti-Inflammatory Role in Human M(IL-4) Macrophages in Response to Mycobacterium tuberculosis |
title_full_unstemmed | The C-Type Lectin Receptor DC-SIGN Has an Anti-Inflammatory Role in Human M(IL-4) Macrophages in Response to Mycobacterium tuberculosis |
title_short | The C-Type Lectin Receptor DC-SIGN Has an Anti-Inflammatory Role in Human M(IL-4) Macrophages in Response to Mycobacterium tuberculosis |
title_sort | c-type lectin receptor dc-sign has an anti-inflammatory role in human m(il-4) macrophages in response to mycobacterium tuberculosis |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006465/ https://www.ncbi.nlm.nih.gov/pubmed/29946317 http://dx.doi.org/10.3389/fimmu.2018.01123 |
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