Toll-like receptor (TLR) signaling plays an essential role in the innate immune response. Activation of TLR signaling through recognition of pathogen-associated molecular patterns leads to the transcriptional activation of genes encoding for pro-inflammatory cytokines, chemokines and co-stimulatory molecules, which subsequently control the activation of antigen-specific adaptive immune response. TLRs have been pursued as potential therapeutic targets for various inflammatory diseases and cancer. Following activation, TLRs induce the expression of a number of protein families, including inflammatory cytokines, type I interferons, and chemokines. Human TLRs were first identified as homologs to the Toll receptor in Drosophila (1); to date, ten proteins have been identified that belong to the human TLR family (2). All TLRs are transmemebrane proteins that consist of a leucine-rich repeat extracellular domain (for recognizing specific pathogens), a transmembrane region, and a Toll-IL-1R domain (for initiating intracellular signaling events). Variations in TLR ligands initiate specific immunological responses. TLR2 recognizes bacterial LAM, BLP, and PGN following their initial interaction with CD14 (3). TLR4 forms a homodimer complex with the MD-2 protein after the initial binding of bacterial LPS to CD14 (4). TLR5 activation occurs following interaction with bacterial flagellin (5). TLR1 and TLR6 function as co-receptors to TLR2 to promote unique signaling mechanisms based on specific pathogen binding (6).  TLR1, TLR2, TLR4, TLR5, and TLR6 are all receptors located on the cell surface; other TLR receptors located within the endosome recognize additional pathogens. TLR3, TLR7/TLR8 and TLR9 are activated by viral dsDNA, viral ssRNA, and bacterial CpG, respectively (7–9). In addition, TLR7 and TLR8 can be activated by the imidazoquinoline compounds imiquimod and R-848.

TLR signaling, regardless of the stimulated receptor, results in the activation of NF-κB and MAP kinases to elicit regulatory responses.  TLR3 and TLR7/TLR8 can also mediate the activation of IRF3 and IRF7 to trigger IFN induction. The signaling events initiated by TLR activation are mediated by unique interaction between TIR domain–containing cytosolic adapters, including myeloid differentiation primary-response protein-88 (MyD88), TIR domain–containing adapter protein (TIRAP), TIR domain–containing adapter–inducing IFNb (TRIF), and TRIF-related adapter molecule (TRAM) (10). MyD88 serves as the central adapter protein associating with and thereby IRAK4 which in turn recruits and phosphorylates IRAK1.  Following interaction with TRAF6, the activated IRAK complex phosphorylates TAB1 and TAK1, which in turn activate the NF-κB and MAPK pathways (11). TLR3 functions through a MyD88-independent pathway by interacting with TRIF, thereby activating a complex of IKKe, TRAF3, and TBK1 that phosphorylates IRF3 and IRF7. (12)

Activation of IRF3 results in the induction of genes (CD40, CD80, and CD86) that stimulate T cell immunogenic responses. IRF7 promotes an antiviral immune response by the induction of IFNa and IFNb gene expression, whereas AP-1 and NF-κB mediate inflammatory responses through the expression of interleukins (IL-1b, IL-6, IL-8, and IL-12), macrophage inflammatory proteins, (MIP-1a and MIP1b), and cytokines (RANTES and TNFa). (13)

References

  1. Lemaitre, B. et al. (1996) Cell 86:973–983.
  2. Oda, K. and Kitano, H. (2006) Molecular Systems Biology 2:2006.0015.
  3. Takeuchi, O. et al. (1999) Immunity 11:443–451.
  4. Hoshino, K. et al. (1999)  J Immunol 162:3749–3752.
  5. Hayashi, F. et al. (2001) Nature 410:1099–1103.
  6. Takeuchi, O. et al. (2002)  J Immunol 169:10–14.
  7. Alexopoulou, L. et al. (2001) Nature 413:732–738.
  8. Diebold, S. et al. (2004) Science 303:1529–1531.
  9. Hemmi, H. et al. (2000) Nature 408:740–745.
  10. Akira, S. and Takeda, K. (2004) Nat Rev Immunol 4:499–511.
  11. Kawai, T. and Akira, S. (2006) Cell Death and Differentiation 13:816–825.
  12. Fitzgerald, K. et al. (2003) Nat Immunol 4:491–496.
  13. Moynagh, P. (2005) Trends in Immunol 26:469–476.