Abstract
Surface-exposed Toll-like receptors (TLRs) such as TLR2 and TLR4 survey the extracellular environment for pathogens. TLR activation initiates the production of various cytokines and chemokines, including type I interferons (IFN-I). Downstream of TLR4, IFNβ secretion is only vigorously triggered in macrophages when the receptor undergoes endocytosis and switches signaling adaptor; surface TLR4 engagement predominantly induces proinflammatory cytokines via the signaling adaptor MyD88. It is unclear whether this dichotomy is generally applicable to other TLRs, cell types, or differentiation states. Here, we report that diverse TLR2 ligands induce an IFN-I response in human monocyte-like cells, but not in differentiated macrophages. This TLR2-dependent IFN-I signaling originates from the cell surface and depends on MyD88; it involves combined activation of the transcription factors IRF3 and NF-κB, driven by the kinases TBK1 and TAK1-IKKβ, respectively. TLR2-stimulated monocytes produced modest IFNβ levels that caused productive downstream signaling, reflected by STAT1 phosphorylation and expression of numerous interferon-stimulated genes. Our findings reveal that the outcome of TLR2 signaling includes an IFN-I response in human monocytes, which is lost upon macrophage differentiation, and differs mechanistically from IFN-I-induction through TLR4. These findings point to molecular mechanisms tailored to the differentiation state of a cell and the nature of receptors activated to control and limit TLR-triggered IFN-I responses.
Highlights
A crucial step for activation of innate immunity is detection of invading pathogens
We found that diverse TLR2 ligands evoke an type I interferon(s) (IFN-I) response in human monocyte-like cells, which is lost upon differentiation into macrophages
Stimulated monocytes transiently express modest levels of IFNb resulting from a signaling cascade (Fig. 7) that 1) occurs upon exposure to TLR2/1 and TLR2/6 ligands, 2) critically depends on the signaling adaptor myeloid differentiation primary response 88 (MyD88), 3) involves TANK-binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3) activity, 4) is complemented by robust transforming growth factor-b–activated kinase-1 (TAK1)/IKKb-induced activation of nuclear factor-kB (NF-kB), rather than of activator protein-1 (AP-1), and 4) does not require TLR2 internalization
Summary
A crucial step for activation of innate immunity is detection of invading pathogens. Cells sense microbes through a set of pattern recognition receptors (PRRs) that recognize conserved microbial structures, known as pathogen-associated molecular patterns (PAMPs) [1]. TLRs initiate signaling events that result in the production of a large variety of cytokines, chemokines, and co-stimulatory molecules, which activate and polarize innate and adaptive immune cells [4, 5]. In plasmacytoid DCs (pDCs), ligation of TLR7 or TLR9 results in the secretion of large quantities of IFN-I, whereas signaling via these receptors in conventional DCs (cDCs) induces much less IFN-I and, instead, mainly triggers the production of proinflammatory cytokines [19, 20]. TLR2 induces IFN-I from the surface of human monocytes ligation, it is, important to dissect the signaling cascades that culminate in the production of IFN-I for individual cell types
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