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

0471917 - ÚMG 2017 RIV US eng J - Článek v odborném periodiku
Aouar, B. - Kovářová, Denisa - Letard, S. - Font-Haro, Albert - Florentin, J. - Weber, J. - Durantel, D. - Chaperot, L. - Plumas, J. - Trejbalová, Kateřina - Hejnar, Jiří - Nunes, J.A. - Olive, D. - Dubreuil, P. - Hirsch, Ivan - Stranska, R.
Dual Role of the Tyrosine Kinase Syk in Regulation of Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells.
PLoS ONE. Roč. 11, č. 6 (2016), č. článku e0156063. ISSN 1932-6203. E-ISSN 1932-6203
Grant CEP: GA ČR GA14-32547S; GA MŠMT(CZ) ED1.1.00/02.0109
Institucionální podpora: RVO:68378050
Klíčová slova: hepatitis-c virus * b-virus * alpha * interferon * secretion * responses
Kód oboru RIV: EB - Genetika a molekulární biologie
Impakt faktor: 2.806, rok: 2016

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)-alpha/beta 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-alpha, TNF-alpha 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-alpha 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-alpha production. Opposing roles of Syk in TLR7/9 and RR pathways may regulate the innate immune response to weaken inflammation reaction.
Trvalý link: http://hdl.handle.net/11104/0269285