Toll-Like Receptor 4 Signalling and Its Impact on Platelet Function, Thrombosis, and Haemostasis

Figure 3

Summary of intracellular TLR4 signalling pathways in nucleated cells. LPS is transferred to CD14 (or albumin), via a process involving LBP and albumin, which transfers LPS to TLR4:MD-2 to complete the heterotetramerisation. There are two major signalling pathways, namely, the MyD88-dependent and -independent pathways, for TLR4 signalling. In the MyD88-dependent pathway, TIRAP (or Mal) enables MyD88 binding to TLR4 and formation of the Myddosome, which contains MyD88, IRAK4, and IRAK1/2. The kinases found at the base of the Myddosome activate TRAF6 and TAK1 followed by the activation of NEMO and its associated kinases. IKKβ stimulates the degradation of inhibitory IκB, which leads to nuclear translocation of NF-κB and transcription of proinflammatory genes. In addition, TAK1 activates JNK1/2, ERK1/2, and p38, which can then stimulate the transcription factor AP-1. In the MyD88-independent pathway, following CD14-dependent internalisation into the endosomes, TRAM and TRIF are recruited to TLR4 before activating TRAF3. Activation of TRAF3 activates TBK1 and IKKε, which phosphorylate and activate the transcription factor IRF3 that stimulates the transcription of anti-inflammatory cytokines.