Figure 2

TLR signaling (an example in macrophages and dendritic cells). TLR2 (TLR2 in association with TLR1 or TLR6), TLR4, TLR5 and TLR11 are localized on the cell surface for ligand recognition. TLR3, TLR7 and TLR9 are localized in the endosome for ligand recognition in the lumen of endosome. All TLRs, except TLR3, recruit MyD88, and TLR1, TLR2, TLR4 and TLR6 recruit the additional adaptor TIRAP which links the TIR domain with MyD88. TLR3 and TLR4 recruit TRIF. TLR4 requires the additional linker adaptor TRAM, which links the TIR domain of TLR4 with TRIF. Stimulation of the cells with TLR1, TLR2, TLR5, TLR6 and TLR11 ligands initiates the MyD88-dependent pathway whereas TLR3 ligands initiate the TRIF-dependent pathway. TLR4 activates both MyD88-dependent and TRIF-dependent pathways. In the MyD88-dependent pathway, MyD88 recruits the IRAK family of proteins and TRAF6. In turn, TRAF6 activates TAK1. The activated TAK1 activates the IKK complex, which activates NF-κB sub-units. The activated TAK1 also activates the MAPK pathway. In the TRIF-dependent pathway, TRIF interacts with RIP1 and TRAF6. Activated TRAF6 and RIP1 activate NF-κB and MAPKs. TRIF also interacts with TRAF3 and activates TBK1/IKKi, which activate IRF3 and IRF7. Cells stimulated with TLR7 and TLR9 ligands activate NF-κB and MAPKs via the MyD88-dependent pathway. To induce type I IFNs, MyD88 associates with the IRAK family of proteins. IRAK1 and IKKα activate IRF7. IRAK1 also interacts with TRAF3 and activates IRF7. The activated NF-κB subunits and IRFs are translocated to the nucleus. NF-κB and MAPKs initiate the transcription of inflammatory cytokine genes whereas IRFs initiate the transcription of type I interferons. (The figure is adapted from (13) and used with permission from Elsevier.)