Abstract
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-κB-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.
Highlights
Macrophages express a variety of specialized pathogen-recognition receptors like toll-like receptors (TLRs) which recognize pathogen-associated molecular patterns derived from invading pathogens or indirectly from infected host cells [1, 2]
Our findings demonstrated that interferon responses are restricted in macrophages after TLR7 activation
Interferon response genes became detectable in TLR7-activated macrophages only after MEK1/2 inhibition, consistent with tumor progression locus 2 (TPL2)-mediated interferon suppression in TLR4- and TLR9-activated macrophages [20]
Summary
Macrophages express a variety of specialized pathogen-recognition receptors like toll-like receptors (TLRs) which recognize pathogen-associated molecular patterns derived from invading pathogens or indirectly from infected host cells [1, 2]. Recognition of double-stranded RNA (dsRNA) by TLR3 and lipopolysaccharide (LPS) by TLR4 in macrophages activate proinflammatory cytokines and interferon regulatory factor 3 (IRF3)-induced interferon [3]. Recognition of CpG DNA by TLR9 and single-stranded RNA (ssRNA) by TLR7 activate mainly proinflammatory cytokines in macrophages. IRF7 induce type I interferons in plasmacytoid dendritic cells (pDCs) [3, 4]. Secreted interferons and cytokines stimulate the janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway to transcribe secondary response genes that are essential for innate and adaptive immunity during anti-viral and anti-tumor responses [5, 6].
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