Dual Role of the Tyrosine Kinase Syk in Regulation of Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells

Dual Role of the Tyrosine Kinase Syk in Regulation of Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells

Crosslinking of regulatory immunoreceptors (RR), such as BDCA-2 (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses production of type-I interferon (IFN)-α/β and other cytokines in response to Toll-like receptor (TLR) 7/9 ligands. This cytokine-inhibitory pathway i...

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Main Authors: Aouar, Besma, Kovarova, Denisa, Letard, Sebastien, Font-Haro, Albert, Florentin, Jonathan, Weber, Jan, Durantel, David, Chaperot, Laurence, Plumas, Joel, Trejbalova, Katerina, Hejnar, Jiri, Nunès, Jacques A., Olive, Daniel, Dubreuil, Patrice, Hirsch, Ivan, Stranska, Ruzena
Format: Online
Language:English
Published: Public Library of Science 2016
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892542/
id pubmed-4892542
recordtype oai_dc
spelling pubmed-48925422016-06-16 Dual Role of the Tyrosine Kinase Syk in Regulation of Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells Aouar, Besma Kovarova, Denisa Letard, Sebastien Font-Haro, Albert Florentin, Jonathan Weber, Jan Durantel, David Chaperot, Laurence Plumas, Joel Trejbalova, Katerina Hejnar, Jiri Nunès, Jacques A. Olive, Daniel Dubreuil, Patrice Hirsch, Ivan Stranska, Ruzena Research Article Crosslinking of regulatory immunoreceptors (RR), such as BDCA-2 (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses production of type-I interferon (IFN)-α/β and other cytokines in response to Toll-like receptor (TLR) 7/9 ligands. This cytokine-inhibitory pathway is mediated by spleen tyrosine kinase (Syk) associated with the ITAM-containing adapter of RR. Here we demonstrate by pharmacological targeting of Syk that in addition to the negative regulation of TLR7/9 signaling via RR, Syk also positively regulates the TLR7/9 pathway in human pDCs. Novel highly specific Syk inhibitor AB8779 suppressed IFN-α, TNF-α and IL-6 production induced by TLR7/9 agonists in primary pDCs and in the pDC cell line GEN2.2. Triggering of TLR9 or RR signaling induced a differential kinetics of phosphorylation at Y352 and Y525/526 of Syk and a differential sensitivity to AB8779. Consistent with the different roles of Syk in TLR7/9 and RR signaling, a concentration of AB8779 insufficient to block TLR7/9 signaling still released the block of IFN-α production triggered via the RR pathway, including that induced by hepatitis B and C viruses. Thus, pharmacological targeting of Syk partially restored the main pDC function—IFN-α production. Opposing roles of Syk in TLR7/9 and RR pathways may regulate the innate immune response to weaken inflammation reaction. Public Library of Science 2016-06-03 /pmc/articles/PMC4892542/ /pubmed/27258042 http://dx.doi.org/10.1371/journal.pone.0156063 Text en © 2016 Aouar et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Aouar, Besma
Kovarova, Denisa
Letard, Sebastien
Font-Haro, Albert
Florentin, Jonathan
Weber, Jan
Durantel, David
Chaperot, Laurence
Plumas, Joel
Trejbalova, Katerina
Hejnar, Jiri
Nunès, Jacques A.
Olive, Daniel
Dubreuil, Patrice
Hirsch, Ivan
Stranska, Ruzena
spellingShingle Aouar, Besma
Kovarova, Denisa
Letard, Sebastien
Font-Haro, Albert
Florentin, Jonathan
Weber, Jan
Durantel, David
Chaperot, Laurence
Plumas, Joel
Trejbalova, Katerina
Hejnar, Jiri
Nunès, Jacques A.
Olive, Daniel
Dubreuil, Patrice
Hirsch, Ivan
Stranska, Ruzena
Dual Role of the Tyrosine Kinase Syk in Regulation of Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells
author_facet Aouar, Besma
Kovarova, Denisa
Letard, Sebastien
Font-Haro, Albert
Florentin, Jonathan
Weber, Jan
Durantel, David
Chaperot, Laurence
Plumas, Joel
Trejbalova, Katerina
Hejnar, Jiri
Nunès, Jacques A.
Olive, Daniel
Dubreuil, Patrice
Hirsch, Ivan
Stranska, Ruzena
author_sort Aouar, Besma
title Dual Role of the Tyrosine Kinase Syk in Regulation of Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells
title_short Dual Role of the Tyrosine Kinase Syk in Regulation of Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells
title_full Dual Role of the Tyrosine Kinase Syk in Regulation of Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells
title_fullStr Dual Role of the Tyrosine Kinase Syk in Regulation of Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells
title_full_unstemmed Dual Role of the Tyrosine Kinase Syk in Regulation of Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells
title_sort dual role of the tyrosine kinase syk in regulation of toll-like receptor signaling in plasmacytoid dendritic cells
description Crosslinking of regulatory immunoreceptors (RR), such as BDCA-2 (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses production of type-I interferon (IFN)-α/β and other cytokines in response to Toll-like receptor (TLR) 7/9 ligands. This cytokine-inhibitory pathway is mediated by spleen tyrosine kinase (Syk) associated with the ITAM-containing adapter of RR. Here we demonstrate by pharmacological targeting of Syk that in addition to the negative regulation of TLR7/9 signaling via RR, Syk also positively regulates the TLR7/9 pathway in human pDCs. Novel highly specific Syk inhibitor AB8779 suppressed IFN-α, TNF-α and IL-6 production induced by TLR7/9 agonists in primary pDCs and in the pDC cell line GEN2.2. Triggering of TLR9 or RR signaling induced a differential kinetics of phosphorylation at Y352 and Y525/526 of Syk and a differential sensitivity to AB8779. Consistent with the different roles of Syk in TLR7/9 and RR signaling, a concentration of AB8779 insufficient to block TLR7/9 signaling still released the block of IFN-α production triggered via the RR pathway, including that induced by hepatitis B and C viruses. Thus, pharmacological targeting of Syk partially restored the main pDC function—IFN-α production. Opposing roles of Syk in TLR7/9 and RR pathways may regulate the innate immune response to weaken inflammation reaction.
publisher Public Library of Science
publishDate 2016
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892542/
_version_ 1613588607193317376

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