their carboxy termini. They then move to the nucleus as active transcription factors. Of the nine IRF family members, IRF3 and IRF7 are particularly important for TLR signaling and expression of antiviral type I interferons. For TLR-3, expressed by macrophages and conventional dendritic cells, the cytoplasmic TIR domain interacts with the adaptor protein TRIF. TRIF interacts with the E3 ubiquitin ligase TRAF3, which, like TRAF6, generates a polyubiquitin scaffold. In TLR-3 signaling, this scaffold recruits a multiprotein complex containing the kinases IKKε and TBK1, which phosphorylate IRF3 (Fig. 3.16). TLR-4 also triggers this pathway by binding TRIF, but the IRF3 response induced by TLR-4 is relatively weak compared with that induced by TLR-3, and its functional role in vivo remains elusive. In contrast to TLR-3, TLR-7, TLR-8, and TLR-9 signal uniquely through MyD88. For TLR-7 and TLR-9 signaling in plasmacytoid dendritic cells, the MyD88 TIR domain recruits the IRAK1/IRAK4 complex as described above. Here, the IRAK complex carries out a distinct function beyond recruiting TRAFs that generate a signaling scaffold. In these cells, IRAK1 can also physically associate with IRF7, which is highly expressed by plasmacytoid dendritic cells. This allows IRF7 to become phosphorylated by IRAK1, leading to induction of type I interferons (see Fig. 3.16). Not all IRF factors regulate type I interferon genes; IRF5, for example, plays a role in the induction of pro-inflammatory cytokines.
The collective ability of TLRs to activate both IRFs and NFκB means that they can stimulate either antiviral or antibacterial responses as needed. In human IRAK4 deficiency, for example, no extra susceptibility to viral infections has been noted. This would suggest that IRF activation is not impaired and the production of antiviral interferons is not affected. TLRs are expressed by different types of cells involved in innate immunity and by some stromal and epithelial cells, and the responses generated will differ in some respects depending on what type of cell is being activated.
3-8 The NOD-like receptors are intracellular sensors of bacterial infection and cellular damage.
The TLRs, being expressed on the cell’s plasma membrane or endocytic vesicles, are primarily sensors of extracellular microbial products. Since the discovery of Toll and the mammalian TLRs, additional families of innate sensors have been identified that detect microbial products in the cytoplasm. One large group of cytoplasmic innate sensors has a centrally located nucleotidebinding oligomerization domain (NOD), and other variable domains that detect microbial products or cellular damage or that activate signaling pathways; collectively, these are the NOD-like receptors (NLRs). Some NLRs activate NFκB to initiate the same inflammatory responses as the TLRs, while other NLRs trigger a distinct pathway that induces cell death and the production of pro-inflammatory cytokines. The NLRs are considered a very ancient family of innate immunity receptors because the resistance (R) proteins that are part of plant defenses against pathogens are NLR homologs.