Toll-like receptors: Organization and signaling pathways

TLR signaling in conventional dendritic cells, macrophages, and plasmacytoid 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, which is transported to the endosome via the endoplasmic reticulum (ER)-localized transporter protein UNC93B for ligand recognition in the lumen of endosome. All TLRs, except TLR3, recruit MyD88, while 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. Dendritic cells or macrophages stimulated with TLR1, TLR2, TLR5, TLR6, and TLR11 ligands initiate 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-kappa-B subunits. 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-kappa-B and mitogen-activated protein kinases (MAPKs). TRIF also interacts with TRAF3 and activates TBK1/IKKi, which activate IRF3 and IRF7. Plasmacytoid dendritic cells stimulated with TLR7 and TLR9 ligands activate NF-kappa-B and MAPKs via the MyD88-dependent pathway. To induce type 1 interferons, MyD88 associates with the IRAK family of proteins. IRAK1 and IKK-alpha activate IRF7. IRAK1 also interacts with TRAF3 and activates IRF7. The activated NF-kappa-B subunits and IRFs are translocated to the nucleus. NF-kappa-B and MAPKs initiate the transcription of inflammatory cytokine genes, whereas IRFs initiate the transcription of type 1 interferons.