The MEK1/2-ERK Pathway Inhibits Type I IFN Production in Plasmacytoid Dendritic Cells

0490084 - ÚMG 2019 RIV CH eng J - Článek v odborném periodiku
Janovec, Vaclav - Aouar, B. - Font-Haro, Albert - Hofman, T. - Trejbalová, Kateřina - Weber, J. - Chaperot, L. - Plumas, J. - Olive, D. - Dubreuil, P. - Nunes, J.A. - Stranska, R. - Hirsch, Ivan
The MEK1/2-ERK Pathway Inhibits Type I IFN Production in Plasmacytoid Dendritic Cells.
Frontiers in Immunology. Roč. 9, únor (2018), č. článku 364. ISSN 1664-3224. E-ISSN 1664-3224
Grant CEP: GA MŠMT(CZ) ED1.1.00/02.0109; GA ČR GA14-32547S
Institucionální podpora: RVO:68378050
Klíčová slova: plasmacytoid dendritic cells * toll-like receptors 7 and 9 (TLR 7/9) * B cell-like receptor signaling * regulatory receptors * blood dendritic cell antigen 2 * MEK1/2 * c-FOS * type I interferon
Obor OECD: Immunology
Impakt faktor: 4.716, rok: 2018

Recent studies have reported that the crosslinking of regulatory receptors (RRs), such as blood dendritic cell antigen 2 (BDCA-2) (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses the production of type I interferons (IFN-I, alpha/ss/omega) and other cytokines in response to toll-like receptor 7 and 9 (TLR7/9) ligands. The exact mechanism of how this B cell receptor (BCR)-like signaling blocks TLR7/9-mediated IFN-I production is unknown. Here, we stimulated BCR-like signaling by ligation of RRs with BDCA-2 and ILT7 mAbs, hepatitis C virus particles, or BST2 expressing cells. We compared BCR-like signaling in proliferating pDC cell line GEN2.2 and in primary pDCs from healthy donors, and addressed the question of whether pharmacological targeting of BCR-like signaling can antagonize RR-induced pDC inhibition. To this end, we tested the TLR9-mediated production of IFN-I and pro-inflammatory cytokines in pDCs exposed to a panel of inhibitors of signaling molecules involved in BCR-like, MAPK, NF-kappa B, and calcium signaling pathways. We found that MEK1/2 inhibitors, PD0325901 and U0126 potentiated TLR9-mediated production of IFN-I in GEN2.2 cells. More importantly, MEK1/2 inhibitors significantly increased the TLR9-mediated IFN-I production blocked in both GEN2.2 cells and primary pDCs upon stimulation of BCR-like or phorbol 12-myristate 13-acetate-induced protein kinase C (PKC) signaling. Triggering of BCR-like and PKC signaling in pDCs resulted in an upregulation of the expression and phoshorylation of c-FOS, a downstream gene product of the MEK1/2-ERK pathway. We found that the total level of c-FOS was higher in proliferating GEN2.2 cells than in the resting primary pDCs. The PD0325901-facilitated restoration of the TLR9-mediated IFN-I production correlated with the abrogation of MEK1/2-ERK-c-FOS signaling. These results indicate that the MEK1/2-ERK pathway inhibits TLR9-mediated type I IFN production in pDCs and that pharmacological targeting of MEK1/2-ERK signaling could be a strategy to overcome immunotolerance of pDCs and re-establish their immunogenic activity.
Trvalý link: http://hdl.handle.net/11104/0284378