Toll-Like Receptor Signaling Pathways

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Overview of Toll-like Receptors

Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors that detect invading pathogens and initiate the innate and adaptive immune response. Different TLRs are expressed on distinct subsets of immune and non-immune cell types, including macrophages, dendritic cells, B cells, T cells, fibroblasts, and epithelial cells. TLRs are activated following recognition of specific conserved pathogen-associated molecular patterns (PAMPs) present in microbial proteins, nucleic acids, lipids, or carbohydrates. Recognition of these molecules by TLRs triggers signal transduction cascades that ultimately induce the expression of pro-inflammatory cytokines and Type I or Type III interferons or IFN-inducible genes. Expression of these cytokines promotes the recruitment of additional leukocytes to the infection site, which together act to eliminate the pathogenic microbes and infected cells. Ten human TLRs have been identified that are expressed either on the cell surface (TLR1, 2, 4, 5, 6, and 10) or in intracellular compartments (TLR3, 7, 8, and 9). Each TLR has a variable number of ligand-sensing leucine-rich repeats at its N-terminal end and a cytoplasmic Toll/IL-1 receptor (TIR) domain. This domain is also conserved in proteins belonging to the IL-1 receptor family and a number of intracellular adaptor proteins that mediate TLR signaling, including MyD88, TRAM, TRIF, and TIRAP. Polymorphisms in TLRs or in specific TLR signaling molecules are associated with increased susceptibility to microbial infections and autoimmune disorders.

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