Toll-Like Receptors

Toll-like receptors (TLRs) are a family of type I transmembrane pattern recognition receptors (PRRs) that are expressed by a number of different immune and non-immune cell types including monocytes, macrophages, dendritic cells, neutrophils, B cells, T cells, fibroblasts, endothelial cells, and epithelial cells. TLRs recognize conserved, pathogen-associated molecular patterns (PAMPs) present in bacterial, fungal, protozoan, or viral proteins, nucleic acids, lipids, or carbohydrates and initiate the innate and adaptive immune response. There are ten functional TLRs in humans and twelve in mice. Of the human TLRs, TLR1, 2, 4, 5, 6, and 10 are expressed on the cell surface and primarily recognize microbial membrane and/or cell wall components, while TLR3, 7, 8, and 9 are expressed in the membranes of endolysosomal compartments and recognize foreign nucleic acids. TLRs have a variable number of ligand-sensing, leucine-rich repeats (LRR) at their N-terminal ends and a cytoplasmic Toll/IL-1 R (TIR) domain. The TIR domain mediates interactions between TLRs and adaptor proteins involved in regulating TLR signaling including MyD88, TRIF, TRAM, and TIRAP/MAL. Signaling pathways activated downstream of these adaptor molecules promote the NF-kappa B- and AP-1-dependent expression of pro-inflammatory cytokines and chemokines, and the IRF3-/IRF7-dependent expression of type I and type III interferons. As a result, additional immune cells are recruited to the infection site and the pathogenic microbes and infected cells are eliminated. Although TLRs provide protection against a wide variety of pathogens, inappropriate or unregulated activation of TLR signaling can lead to chronic inflammatory and autoimmune disorders.

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