of pro-inflammatory cytokines, type I interferons, chemokines and other co-stimulatory molecules. There are 10 known Toll-like receptors in mammals of which receptors 1 to 9 are conserved (shown); Tlr10 is expressed in humans and rats but not in mice, rodents express Tlr11 and Tlr12 while Tlr13 is only expressed in mice. A variety of immune cells and also non-immune cells express TLRs. The receptors are type I transmembrane glycoproteins containing extracellular leucine rich repeats (LRRs) involved in PAMP recognition and intracellular Toll/interleukin-1 receptor (TIR) domain involved in the interaction with downstream molecules. Several receptors are anchored at the plasma membrane and recognize components of microbial surface and membranes as well as viral and/or fungal elements. Others are anchored to endosomes and other intracellular vesicles and respond to nucleic acids. The ER resident Unc93b1 protein is critical for the transport of these receptors. Tlrs form homo- and heterodimers; for instance, Tlr2 heterodimerizes with either Tlr1 or Tlr6, Tlr3 or Tlr4 form homodimers with Tlr4 requiring an accessory protein Ly96 (MD-2) to bind its ligand LPS (lipopolysaccharide). Upon binding by lipopolysaccharide binding protein Lbp and formation of a ternary LPS-Lbp-Cd14 complex, LPS is 'transferred' to the Tlr4-Ly96 complex. Crystal structures of ligand-bound extracellular domains show the unique horseshoe topology (described as 'M' or 'm'). The mechanisms thereby receptors recognize different molecules are poorly understood. All receptors rely on adaptor proteins to initiate downstream events. The main adaptor protein is Myd88 to which many receptors bind directly while others require Tirap adaptor. Ticam1, also known as Trif is the adaptor utilized by Tlr3 and also by Tlr4 which needs Ticam2. Tlr4 is the only receptor that employs both the Myd88-dependent and Myd88-independent routes albeit with different kinetics. The Myd88-dependent route of Tlr4 is believed to be involved in the early-phase activation of Nf-kappaB and MAP kinase cascades. Subsequently Tlr4 is endocytosed to endosomes to activate second-phase Nf-KappaB and MAP signaling via Traf6, and Irf3 activation via Traf3 in the Myd88-independent route. Myd88 recruits Irak4 which then recruits and activates Irak1 and 2. The activated complex recruits the E3 ubiquitin ligase Traf6 which together with the E2 enzymes Ube2n and Ube2v1 activates Map3k7 (Tak1) and associated proteins via K63-linked ubiquitination. Activated Map3k7 prompts Nf-kappaB and MAP kinase signaling cascades. Myd88, downstream of Tlr7 and 9 can also stimulate the production of type I interferons. Ticam1 interacts with Traf6, Ripk1 and Traf3; downstream of Traf6, activation of Tak1 proceeds via mechanisms similar to those in MyD88-dependent route. Ripk1, which interacts with Tradd, leads to activation of Nf-kB, whereas Traf3, via downstream kinases such as Tbk1, activates Irf3 which then translocates to the nucleus to prompt the expression of type I interferons. Numerous feedback loops along with endogenous and exogenous negative regulators modulate the toll-like cascades. To see the ontology report for annotations, GViewer and download, click here [click to see associated GO term - GO:0008063, KEGG map map04620 and entry at Reactome - REACT_6966.6]...(less)