The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation

Figure 1

TLR4 intracellular signaling pathways. TLR signaling is triggered by ligand-induced dimerization of the receptors. TIR domains of TLR4 recruit TIR domain-containing adaptor proteins MyD88 and MAL (MyD88-dependent pathway) or TRIF and TRAM (MyD88-independent pathway). MyD88-dependent pathway involves the recruitment and the activation of IRAKs (IRAK1, IRAK2, and IRAK4) and TRAF6 that induce TAK1 activation. TAK1, in turn, leads to MAP kinase kinase- (MKK-) mediated activation of MAPKs (p38, JNK, and ERK1/2) and activation of IKK complex. MAPKs and IKK complex induce activation and translocation in the nucleus of transcription factors such as NF-B and AP-1. MyD88-independent pathway involves TRIF and TRAM adaptor proteins and, via TRAF3, the recruitment of TBK1/IKKε, followed by the activation and translocation in the nucleus of the transcription factor IRF3. MyD88-dependent pathway induces production of proinflammatory cytokines, and MyD88-independent pathway induces the production of type I interferons.