Toll-like receptors (TLRs) are a group of highly conserved pathogen recognition receptors which initiate and regulate the immune response by controlling cytokine and chemokines expression.
Mammalian and avian lineages diverged from the common ancestor approximately 300 millions years ago. Although most of the genes encoding proteins of the chicken TLR cascade molecules have not been cloned and characterized directly, analyses of the chicken genome sequence has defined ten TLRs [Lynn et al. 2003, Temperley ND et al. 2008]. The avian TLR repertoire consists of single orthologs of mammalian TLRs 3, 4, 5 and 7 and distinct new chicken genes TLR15 and TLR21. The TLR2 subfamily is represented by tandemly duplicated avian TLR2 and TLR1 genes and consists of two isoforms of each gene - TLR2 type1 and 2, TLR1 type1 and 2. No functional orthologs of mammalian TLR8, TLR9 and TLR10 have been detected in the chicken genome. However, chicken heterophils and spleen cells are responsive to the broad range of mammalian TLR antagonists including ligands that stimulate mammalian TLR7/8 and TLR9 [Schwarz et al. 2007, He et al. 2006, Kogut et al. 2007].
TLR signaling pathways are highly conserved among vertebrates and the chicken proteins involved in the TLR signaling cascade show moderate to high identity with their human counterparts [Yilmaz et al. 2005, Temperley et al. 2008, Cormican et al. 2009]. Thus, a homology-based strategy was used to reconstruct most parts of the chicken TLR pathways in this Reactome module.
All TLRs share a similar structure consisting of N-terminus ectodomain with several leucine-rich regions (LRR), one or two trans-membrane domains and an intracellular C-terminus Toll/Interleukin-1 receptor domain (TIR).
Activation of TLR pathways occurs upon recognition and interaction with conserved motifs expressed by invading microbes, also known as pathogen-associated molecular patterns (PAMPs). Each TLR recognizes specific PAMPs.
Upon PAMP binding TLRs form heterodimers (TLR2 subfamily) or homodimers (all other TLRs). Activated TLRs recruit one or several TIR adaptor proteins myeloid differentiation primary response gene 88 (MyD88), TIR domain containing adaptor protein (TIRAP or MAL), TIR domain-containing adapter protein inducing IFN-beta (TRIF or TIKAM-1), and TRIF related adaptor molecule (TRAM). The fifth known adaptor SARM binds TIR as a negative competitor to TRIF.
All TLRs except TLR3 can initiate downstream signaling through MyD88 adaptor protein. In the MyD88-dependent pathway, once the adaptor is bound to TLR, it leads to recruitment of IL1 receptor associated kinase family IRAK, followed by activation of tumour necrosis factor receptor-associated factor 6 (TRAF6). TRAF6 is an ubiquitin E3 ligase, which in turn induces TGF-beta activating kinase 1 (TAK1) autophosphorylation. Once activated, TAK1 can ultimately mediate the induction of the transcription factor NF-kB or the mitogen-activated protein kinases (MAPK), such as JNK, p38 and ERK. This results in the translocation of the activated NF-kB and MAPKs to the nucleus and the initiation of appropriate gene transcription leading to the production of many proinflammatory cytokines and antimicrobial peptides.
In contrast to other TLRs, TLR3 functions only through the MyD88-independent signaling cascade, recruiting TRIF, which in turn leads to the interferon regulatory factor 3 or 7 (IRF3/7) activation. Activated IRF3 or 7 mediates innate anti-viral responses through interferon-beta expression.
Mammalian TLR4 can ultimately utilize both MyD88-dependent (controlled by the MyD88-TIRAP pair of adaptors) and MyD88-independent (controlled by TRAM-TRIF adaptor proteins) signaling pathways, in contrast, chicken TLR4 signaling is mediated by MyD88-TIRAP exlusively.