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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02020

MEK1/2 Inhibitors Unlock the Constrained Interferon Response in Macrophages through IRF1 Signaling

  • 1Department of Biological Sciences, National University of Singapore, Singapore
  • 2Biological Sciences, National University of Singapore, Singapore

Macrophages are immune sentinels essential for pathogen recognition and immune defense. Nucleic acid-sensing toll-like receptors like TLR7 activate tailored proinflammatory and interferon responses in macrophages. Here we found that TLR7 activation constrained itself and other TLRs from inducing interferon response genes in macrophages through MAPK kinase 1/2 (MEK1/2)-dependent IRF1 inhibition. Downstream of the MEK1/2-ERK pathway, TLR7-activated macrophages induced interleukin-10 (IL-10), a signal transducer and activator of transcription 3 (STAT3) signaling axis, which constrained the expression of interferon response genes, immunomodulatory cytokines and chemokines. Nevertheless, MEK1/2 inhibitors unlocked an IRF1-interferon signature response in an NF-B-dependent manner. Deficiency in interferon regulatory factor 1 (Irf1) completely abrogated the interferon response and prevented the reprogramming of macrophages into an immunostimulatory phenotype. As a proof of concept, combination treatment with a TLR7 agonist and MEK1/2 inhibitor synergistically extended the survival of wild-type but not Irf1-deficient melanoma-bearing mice. In a retrospective study, higher expression of Irf1 and interferon response genes correlated with more favorable prognosis in patients with cutaneous melanoma. Our findings demonstrated how MEK1/2 inhibitor unlocks IRF1-mediated interferon signature response in macrophages, and the therapeutic potentials of combination therapy with MEK1/2 inhibitor and TLR7 agonist.

Keywords: macrophage, MAPK, mek inhibitor, TLR7 agonist, IRF1, interferon

Received: 27 May 2019; Accepted: 09 Aug 2019.

Copyright: © 2019 YANG and Ding. 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(s) 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: Prof. Jeak Ling Ding, National University of Singapore, Biological Sciences, Singapore, 117543, Singapore, dbsdjl@nus.edu.sg