An alternative model for type I interferon induction downstream of human TLR2

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 if 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 is dependent 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 (ISGs). 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.

TIRAP/Mal Positively Regulates TLR8-Mediated Signaling via IRF5 in Human Cells

“…Indeed, TIRAP silencing led to decreased TNF , IL-6 , IL-1β , IL-12A , and IL-12B mRNA expression following TLR2 and TLR4 stimulation ( Figure S1a,b ). TLR2 did not induce IFNβ mRNA expression or secretion in human MDMs, in agreement with earlier studies [ 29 ]. Notably, in the case of TLR2 and TLR4 stimulation, we have not observed a significant effect on the early induction of pro-inflammatory cytokines ( Figure S1a,b ), which could be due to the still-sufficient amount of residual TIRAP protein for the initiation of signaling, despite a marked decrease in TIRAP-protein expression in silenced MDMs ( Figure S1c ).…”

Multivariate Analysis Reveals That Unsubstituted β-Ring and C8-Keto Structures Are Important Factors for Anti-Inflammatory Activity of Carotenoids

“…The detailed signaling pathway of the P3C-IRF axis, the characteristic target of C8keto carotenoids, is still controversial; however, recently, it has been reported that P3C induces IRF activation in THP1-Dual monocytes [39]. Thus, we considered that P3C itself, rather than any possible contaminants, induced IRF activation under our experimental conditions.…”

Anti-Inflammatory Effect of an O-2-Substituted (1-3)-β-D-Glucan Produced by Pediococcus parvulus 2.6 in a Caco-2 PMA-THP-1 Co-Culture Model

“…However, this was not the case, since addition of LPS to the lower compartment in the absence of macrophages, as well as direct stimulation of the apical membrane of the enterocytes with LPS in the presence of PMA-THP-1 cells, did not elicit an inflammatory response (data not shown). The membranes of the two cell lines carry TLR-4 receptors, which recognize LPS and trigger inflammation as well as the increase of gut barrier permeability in human models [19,[39][40][41][42]. However, under our conditions, LPS alone was not able to activate the inflammatory response in Caco-2 cells monolayer.…”