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Related Pathways Toll-like Receptor Signaling NF-kappa B Signaling TREM1 Signaling View All Pathways

Synonyms: CD281, DKFZp547I0610, DKFZp564I0682, KIAA0012, MGC104956, MGC126311, MGC126312, rsc786, TIL, TLR1, TOLL LIKE RECEPTOR 1

Toll-like Receptors Pathway

Pathogens such as bacteria, fungi, viruses and protozoa constitutively express sets of class-specific mutation-resistant molecules called pathogen-associated molecular patterns (PAMP). Host cells have developed multilevel innate immune response systems that recognize these molecular patterns through pattern recognition receptor (PRR) motifs. Three PRR receptor families include the Toll-like receptors (TLR), NOD-like receptors (NLR) and RIG-I-like receptors (RLR), wherein the Toll-like receptors survey at the level of cell membranes (plasma and endosome) and the NLR and RLR receptors are intracellular.

Toll-like receptors (TLR) are mammalian homologues of Drosophila Toll receptors. TLRs are transmembrane proteins that contain extracellular domains composed of leucine-rich regions that interact with specific PAMP ligands. The cytoplasmic domains of TLRs, which are homologous to the interleukin-1 receptor (IL-1R) signaling domain, are the called Toll/interleukin-1 receptor (TIR) domains. PAMP-specific activation of TLRs converges at the level of TIR domain signaling to induce the activation of NFkappaB and inflammatory gene expression to clear infectious agents. The TIR domain has been linked to five adaptor molecules; MyD88, Mal (MyD88 adaptor-like)/TIRAP (TIR domain-containing adaptor protein), Trif (TIR-domain-containing adaptor inducing interferon-beta), TRAM (Trif-related adaptor molecule) and SARM (SAM and ARM-containing protein).

The TLRs are categorically divided into two membrane receptors groups. TLR1, TLR2, TLR4, TLR5, TLR6, TLR10, TLR11, TLR12 and TLR13 are typically associated with the cell surface. TLR3, TLR7, TLR8 and TLR9 are found primarily on endosomal membranes. Phylogenetically the TLRs are divided into six families; TLR1, TLR3, TLR4, TLR5, TLR7 and TLR11. TLRs are differentially activated by a variety of PAMPs such as bacterial DNA, LPS, peptidoglycan, teichoic acids, flagellin, pilin, viral dsRNA and fungi zymosan. For example, TLR2 recognizes soluble peptidoglycan, lipoteichoic acid and whole Gram-positive bacteria and TLR4 responds to the Gram-negative component lipopolysaccharide (LPS). Activated TLRs differentially trigger the expression of cytokines such as the interferons; the interleukins; IL-2, IL-6, IL-8, IL-12, IL-16, and TNFalpha.