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 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.
Centre de Recherche en Cancérologie de Marseille, Inserm U1068, Marseille, France.|CNRS, UMR7258, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|Aix-Marseille Université, UM105, Marseille, France.
Besma
B
Aouar
Centre de Recherche en Cancérologie de Marseille, Inserm U1068, Marseille, France.|CNRS, UMR7258, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|Aix-Marseille Université, UM105, Marseille, France.|Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.|Department of Genetics and Microbiology, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
Denisa
D
Kovarova
Centre de Recherche en Cancérologie de Marseille, Inserm U1068, Marseille, France.|CNRS, UMR7258, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|Aix-Marseille Université, UM105, Marseille, France.|AB Science, Paris, France.
Sebastien
S
Letard
Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.|Department of Genetics and Microbiology, Faculty of Science, Charles University in Prague, Prague, Czech Republic.|Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.
Albert
A
Font-Haro
Centre de Recherche en Cancérologie de Marseille, Inserm U1068, Marseille, France.|CNRS, UMR7258, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|Aix-Marseille Université, UM105, Marseille, France.
Jonathan
J
Florentin
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.
Jan
J
Weber
Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Lyon, France.
David
D
Durantel
UJF, INSERM U823, University Grenoble Alpes, EFS Rhone-Alpes, Grenoble, France.
Laurence
L
Chaperot
UJF, INSERM U823, University Grenoble Alpes, EFS Rhone-Alpes, Grenoble, France.
Joel
J
Plumas
Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
Katerina
K
Trejbalova
Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
Jiri
J
Hejnar
Centre de Recherche en Cancérologie de Marseille, Inserm U1068, Marseille, France.|CNRS, UMR7258, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|Aix-Marseille Université, UM105, Marseille, France.
Jacques A
JA
Nunès
Centre de Recherche en Cancérologie de Marseille, Inserm U1068, Marseille, France.|CNRS, UMR7258, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|Aix-Marseille Université, UM105, Marseille, France.
Daniel
D
Olive
Centre de Recherche en Cancérologie de Marseille, Inserm U1068, Marseille, France.|CNRS, UMR7258, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|Aix-Marseille Université, UM105, Marseille, France.
Patrice
P
Dubreuil
Centre de Recherche en Cancérologie de Marseille, Inserm U1068, Marseille, France.|CNRS, UMR7258, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|Aix-Marseille Université, UM105, Marseille, France.|Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.|Department of Genetics and Microbiology, Faculty of Science, Charles University in Prague, Prague, Czech Republic.|Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.
Ivan
I
Hirsch
Centre de Recherche en Cancérologie de Marseille, Inserm U1068, Marseille, France.|CNRS, UMR7258, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|Aix-Marseille Université, UM105, Marseille, France.
Ruzena
R
Stranska
D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000072377:Syk Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*
D016207:Cytokines; D047428:Protein Kinase Inhibitors; D051193:Toll-Like Receptors; D000072377:Syk Kinase