3-7 TLRs activate NFκB, AP-1, and IRF transcription factors to induce the expression of inflammatory cytokines and type I interferons.
Signaling by mammalian TLRs in various cell types induces a diverse range of intracellular responses that together result in the production of inflammatory cytokines, chemotactic factors, antimicrobial peptides, and the antiviral cytokines interferon-α and -β (IFN-α and IFN-β), the type I interferons. TLR signaling achieves this by activating several different signaling pathways that each activate different transcription factors. As mentioned earlier, ligand-induced dimerization of two TLR ectodomains brings the cytoplasmic TIR domains together, allowing them to interact with the TIR domains of cytoplasmic adaptor molecules that initiate intracellular signaling. There are
Pattern recognition by cells of the innate immune system.
four such adaptors used by mammalian TLRs: MyD88, MAL (also known as TIRAP), TRIF, and TRAM. It is significant that the TIR domains of the different TLRs interact with different combinations of these adaptors (Fig. 3.14). Most TLRs interact only with MyD88, which is required for their signaling.
Fig. 3.13 TLR-4 recognizes LPS in association with the accessory protein MD-2. Panel a: a side view of the symmetrical complex of TLR-4, MD-2, and LPS. TLR-4 polypeptide backbones are shown in green and dark blue. The structure shows the entire extracellular region of TLR-4, composed of the LRR region (shown in green and dark blue), but lacks the intracellular signaling domain. The MD-2 protein is shown in light blue. Five of the LPS acyl chains (shown in red) are inserted into a hydrophobic pocket within MD-2. The remainder of the LPS glycan and one lipid chain (orange) make contact with the convex surface of a TLR-4 monomer. Panel b: the top view of the structure shows that an LPS molecule makes contact with one TLR-4 subunit on its convex (outer) surface, while binding to an MD-2 molecule that is attached to the other TLR-4 subunit. The MD-2 protein binds off to one side of the TLR-4 LRR region. Panel c: schematic illustration of relative orientation of LPS binding to MD-2 and TLR-4. Structures courtesy of Jie-Oh Lee.
Fig. 3.14 Mammalian TLRs interact with different TIR-domain adaptor molecules to activate downstream signaling pathways. The four signaling adaptor molecules used by mammalian TLRs are MyD88 (myeloid differentiation factor 88), MAL (MyD88 adaptor-like, also known as TIRAP, for TIR-containing adaptor protein), TRIF (TIR domain-containing adaptor-inducing IFN-β), and TRAM (TRIF-related adaptor molecule). All TLRs interact with MyD88, except TLR-3, which interacts only with TRIF. The table indicates the known pattern of adaptor interactions for the known TLRs.
TLR-3 interacts only with TRIF. Other TLRs use either MyD88 paired with MAL, or TRIF paired with TRAM. Signaling by the TLR-2 heterodimers (TLR-2/1 and TLR-2/6) requires MyD88/MAL. TLR-4 signaling uses both of these adaptor pairs, MyD88/MAL and TRIF/TRAM, which is used during endosomal signaling by TLR-4. Importantly, the choice of adaptor influences which of the several downstream signals will be activated by the TLR.