TLR/IL-1R signalling pathways. Once activated by their respective ligands, IL-1R, IL-18R, and TLRs engage with one or more adaptor proteins. These adaptors, namely, MyD88, MAL/TIRAP, TRIF, and TRAM are recruited, in various combinations, to the cytoplasmic domains of the receptors through homophilic interactions between Toll/IL-1 receptor (TIR) domains present in each receptor and each adaptor. TIRAP is required to act as a bridge for MyD88 in TLR2 and TLR4 signalling, while TRIF is used in TLR3 signalling and, in association with TRAM, in TLR4 signalling. In the MyD88-dependent pathway, MyD88 associates with IRAK4, IRAK1 and/or IRAK2. IRAK4 in turn phosphorylates IRAK1 and IRAK2 and promotes their association with TRAF6, which serves as a platform to recruit the kinase TAK1. Once activated, TAK1 activates the IKK complex, composed of IKKα, IKKβ and NEMO (IKKγ), which catalyzes phosphorylation and subsequent degradation of IκB rendering NF-κB (i.e., p50/p65) free to translocate from the cytosol to the nucleus and activate NF-κB-dependent genes. The transcription factor IRF7 is also activated downstream of TLRs 7, 8, and 9, leading to its translocation into the nucleus and to activation of IFNα and IFN-inducible genes. TLR3 and TLR4 both signal through the adaptor TRIF, which interacts with TRAF3 to activate the noncanonical IKKs, TBK1, and IKKε resulting in the dimerization and activation of IRF3, which then translocates into the nucleus activating the transcription of IFNβ and IFN-inducible genes.
