The Role of Toll-Like Receptors in Skin Host Defense, Psoriasis, and Atopic Dermatitis

Figure 1

MyD88-dependent and TRIF-dependent TLR signaling pathways. Ligand binding of TLRs by their respective ligands induces dimerization of TLRs and initiates MyD88-dependent or TRIF-dependent signaling cascades. The presence of coreceptors, such as CD14 for TLR2, TLR3, TLR4, TLR7, and TLR9, CD36 for TLR2 and TLR6, and CD44 for TLR4, promotes ligand binding efficiency to TLRs. MD2 is a receptor component associated with TLR4 and enables TLR4 to respond to LPS. Activation of TLR1-TLR2 by the lipopeptide Pam3CSK, TLR2-TLR6 by the lipopeptide Malp2, TLR5 by flagellin, or TLR4 by LPS recruits MyD88 through the adaptor molecule TIRAP. MyD88 then recruits and activates the IRAK complex, which in turn activates TRAF6, which serves as a platform to recruit and activate TAK1 in cooperation with TAB1-3. Once activated, TAK1 activates the IKK-NFκB pathway and the MAPK- (including P38, ERK1/2, and JNK) AP1 pathway. Activated NFκB or AP1 translocates to the nucleus, driving the transcription of genes encoding proinflammatory cytokines, antimicrobial peptides, and costimulatory molecules. Activation of endosomal TLR7 by ssRNA or guanosine, TLR8 by ssRNA, or TLR9 by CpG-DNA not only initiates the MyD88-TRAF6-dependent activation of AP1 and NFκB but also triggers the IRAK-, TRAF6-, TRAF3-, and IKKα-dependent activation of IRF7, translocation of which induces the transcription of type1 interferon genes including IFNα and IFNβ. In contrast, activation of TLR3 by dsRNA initiates the TRIF-dependent pathway, whereas TLR4 activation induces both MyD88- and TRIF-dependent pathways. Once recruited to the intracellular domain of TLRs by TRAM, TRIF initiates a TRAF3-dependent activation of the TBK1-type 1 IFN pathway and/or a TRAF6-dependent activation of the TAK1-proinflammatory cytokine pathway. The TRAF3-dependent activation of TBK1 and IKKε and TBK1-mediated activation of AKT result in the coordinate activation of the transcription factor IRF3, which translocates to the nucleus and induces the transcription of type 1 interferon genes upon activation. Pam3CSK4: tripalmitoyl-S-glycero-Cys-(Lys)4; Malp2: macrophage-activating lipopeptide-2; LPS: lipopolysaccharide; dsRNA: double-stranded RNA; ssRNA: single-stranded RNA; CpG: deoxycytidyl-phosphate-deoxyguanosine; MyD88: myeloid differentiation primary response gene 88; TIRAP: TIR domain-containing adaptor protein; TRAM: TRIF-related adaptor molecule; TRIF: TIR domain-containing adaptor inducing IFNβ; TRAF: TNFR-associated factor; IRAK: IL1R-associated kinase; TAK: transforming growth factor beta-activated kinase 1; TAB: TAK1-binding protein; IKK: inhibitor of nuclear factor kappa-B kinase; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; IκB: inhibitor of NFκB; TBK1: TANK binding kinase 1; AMPs: antimicrobial peptides.