Toll-like receptors (TLR) - the Toll/IL-1R superfamily
Initial recognition of microbes, as they enter the body, is based on germ line-encoded pattern recognition receptors (PRR) that selectively bind to essential components of pathogens, so-called pathogen-associated molecular patterns (PAMP). This allows an immediate response to the microbial invasion before the development of active immunity.
The Toll-like receptors (TLR), conserved throughout evolution, are the primary sensors of this innate (natural) immunity and thus play a crucial role in our primary defense against infections. However, activation of TLRs may also cause tissue injury including manifestations of septic shock and host cell apoptosis. Hence, the activation of TLRs in the context of infectious disease may also contribute to immunopathology; see Crohn's disease.
As shown below, TLR4, along with CD14, serves as a major PRR for signaling initiated by a major PAMP, bacterial lipopolysaccharide (LPS), originating from cell wall components of Gram-negative bacteria. The signal transduction pathways resemble those triggered by the type I IL-1 receptor (IL-1RI), a member of an expanding receptor superfamily of critical importance in innate immune and inflammatory responses.
LEFT: The Toll/IL-1R superfamily
The intracellular components are similar and contain the Toll/IL-1 receptor homology domain (TIR). In contrast, the extracellular parts have no homology and binds to distinct ligands. The 10 known TLRs differ primarily by the variable lengths of their extracellular components.
RIGHT: The LPS-receptor complex, and some of the intracellular signaling pathways
TLR4 is activated by LPS after it binds to LPS-binding protein (LBP) and CD14. The soluble molecule MD-2 is essential for TLR4 signaling. Other factors involved are the CD11/CD18 complex of adhesion molecules, CD55 and membrane ion channels. After activation, the TLR4 homodimer signals the adaptor protein MyD88 through the TIR domain, and this in turn recruits the IL-1R-associated kinase (IRAK) to the receptor complex. IRAK then autophosphorylates and activates TRAF6, which through intermediate kinases leads to phosphorylation and degradation of the NF-kappaB inhibitor, IkappaB. NF-kappaB is now free to translocate to the nucleus to activate target genes.
Other abbreviations: IL-1RAcP: IL1R accessory protein. IL-18R: IL-18 receptor.
