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Innate Immunity Pathways in Autoimmune Diseases

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Front. Immunol. | doi: 10.3389/fimmu.2018.00364

The MEK1/2-ERK pathway inhibits type I IFN production in plasmacytoid dendritic cells

 Vaclav Janovec1, 2,  Besma Aouar3, Albert Font-Haro1, 4,  Tomas Hofman1, Katerina Trejbalova4,  Jan Weber2,  Laurence Chaperot5, 6, 7, Joel Plumas5, 6, 7,  Daniel Olive3,  Patrice Dubreuil3,  Jacques A. Nunes3,  Ruzena Stranska3 and  Ivan Hirsch1, 2, 3, 4*
  • 1Charles University, Czechia
  • 2Institute of Organic Chemistry and Biochemistry (ASCR), Czechia
  • 3UMR7258 Centre de recherche en cancérologie de Marseille (CRCM), France
  • 4Institute of Molecular Genetics (ASCR), Czechia
  • 5Université Grenoble Alpes, France
  • 6Centre Hospitalier Universitaire de Grenoble, France
  • 7INSERM UMR5309 Institut pour l'Avancée des Biosciences (IAB), France

Recent studies have reported that the crosslinking of regulatory receptors (RRs), such as BDCA-2 (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses the production of type I interferons (IFN-I, α/β/ω) 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 (HCV) particles, or BST-2 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 proinflammatory cytokines in pDCs exposed to a panel of inhibitors of signaling molecules involved in BCR-like, MAPK, NF-ĸB, 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 (PMA)-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.

Keywords: innate immunity, plasmacytoid dendritic cells, Toll-like receptors 7 and 9 (TLR7/9), B cell-like receptor (BCR) signaling, regulatory receptors, BDCA-2, MEK1/2, c-fos, type I IFN

Received: 20 Nov 2017; Accepted: 09 Feb 2018.

Edited by:

Moncef Zouali, Institut National de la Santé et de la Recherche Médicale (INSERM), France

Reviewed by:

Nadine VARIN-BLANK, Institut National de la Santé et de la Recherche Médicale (INSERM), France
Junji Xing, Houston Methodist Research Institute, United States  

Copyright: © 2018 Janovec, Aouar, Font-Haro, Hofman, Trejbalova, Weber, Chaperot, Plumas, Olive, Dubreuil, Nunes, Stranska and Hirsch. 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.

* Correspondence: PhD. Ivan Hirsch, Charles University, Prague, Czechia, Ivan.Hirsch@inserm.fr