Immune response - TLR3 and TLR4 induce TICAM1-specific signaling pathway

Role of TLRs 3 and 4 in cell antiviral response: TICAM1-specific signaling pathways

Toll-like receptors (TLR) initiate signaling cascades through recognition of a variety of microbial components, thus serving as an important link between innate and adaptive immune responses. Each TLR recognizes distinct ligands by means of its leucine-rich repeats and elicits different, but often overlapping immune responses [1].

TLR3-induced signaling pathways are triggered by binding of virus-derived double-stranded RNA [1], whereas TLR4 becomes activated after binding to number of bacterial cell wall components: Lipopolysaccharide (LPS) [1], Pulmonary surfactant-associated protein A (PSAP) [2], Paclitaxel [3], Fibronectin [4], Pneumolysin [5].

Although Myeloid differentiation primary response gene 88 (MyD88)-dependent signaling pathway is common for all TLRs, TLR3- and TLR4-induced activation of the transcription factor nuclear factor kappa B (NF-kB) can be mediated by some alternative adaptors. It can be activated by TLR3 ligands via Toll-like receptor adaptor molecule 1 (TRIF (TICAM1)) [1]. TLR4 signaling can also be mediated by TRIF (TICAM1), which binds to TLR4 adaptor Toll-like receptor adaptor molecule 2 (TRAM) [6]. In addition TLRs are able to induce autophagy through TRIF (TICAM1) - Beclin 1 interaction [7]. TLR4 activates NF-kB independently of TRIF (TICAM1) through its other adaptor, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP (Mal)) [8]. TRIF (TICAM1)-dependent NF-kB activation is mediated either by TNF receptor-associated factor 6 (TRAF6) or by Receptor TNFRSF-interacting serine-threonine kinase 1 (RIPK1)-induced kinase cascade [1]. Moreover, TRIF (TICAM1) causes activation of transcription factor Interferon regulatory factor 3 (IRF3) [9]. Both IRF3 and NF-kB regulate expression of such proinflammatory molecules as Interferon alpha and beta (IFN-alpha and IFN-beta), thus mediating the antiviral action of interferon.

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