Targeting TLR/IL-1R Signalling in Human Diseases

Figure 2

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 IKK$\alpha$, IKK$\beta$  and NEMO (IKK$\gamma$), which catalyzes phosphorylation and subsequent degradation of I$\kappa$B rendering NF-$\kappa$B (i.e., p50/p65) free to translocate from the cytosol to the nucleus and activate NF-$\kappa$B-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 IFN$\alpha$ and IFN-inducible genes. TLR3 and TLR4 both signal through the adaptor TRIF, which interacts with TRAF3 to activate the noncanonical IKKs, TBK1, and IKK$\epsilon$ resulting in the dimerization and activation of IRF3, which then translocates into the nucleus activating the transcription of IFN$\beta \hspace{0.17em}\hspace{0.17em}$and IFN-inducible genes.