Figure 1.

MyD88 dependent and Myd88 independent signaling pathways for the TLRs and helicases. A. Intracellular pathways for MyD88 independent TLR3 nuclear signal transduction initiated by TRIF binding to the TIR of the TLR3 homodimer. TLR3 monomers dimerize with binding of the dsRNA ligand. Activated TRIF initiates two pathways. The first results in the transitory induction of the IFNs. The second is a species variable pathway (rodents ≫primates) that operates though NFκB (dashed line), which transiently induces the production of inflammatory cytokines. The adapter protein cascade initiated by TRIF (TIR-domain-containing adapter-inducing interferon) includes TBK1 (TANK-binding kinase 1 binds to TRAF3), TRAF1/3 (TNF receptor associated factors), NAP1 (Nck-associated protein 1), IKK (IκB kinase), IKKε (inhibitor of IκB kinase), P13K (Phosphoinositide 3-kinase), IRF3/7 (interferon regulatory transcription factors), TAK1 (protein kinase of MLK family), TAB1 (TGF-β activated kinase 1), RIP1 (Receptor-interacting [TNFRSF] kinase 1), NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells), IκB (inhibitor NFkB). The ectodomain of TLR3 consists of a horseshoe shaped structure populated by 23 leucine-rich β-sheets (orange disks) connected by non-ordered chains containing RNA binding residues. The transmembrane a-helices (solid orange) connect the ectodomain to the cytoplasmic TIR domain (dark green). The phosphorylated TIR binds TRIF to initiate the adapter protein cascade. B. Intracellular pathways for MyD88 dependent for TLR 1/2 and 1/6 heterodimers and TLR 4–10 homodimers with the diverse PAMP ligands represented by a green bar is not necessarily as accurate in placement as is dsRNA with TLR3 in 1A. TLR4 uses both the MyD88 dependent and independent pathways. Reproduced from Mitchell WM, et al .Discordant Biological and Toxicological Species Responses to TLR3 Activation. Am J Path 2014; 184: 1062–72.