Toll-Like Receptors (TLRs)

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    Immunology Background

    About Toll-Like Receptors (TLRs)

    Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs) that initiate the innate immune response by sensing conserved molecular patterns for early immune recognition of a pathogen. The typical TLRs are type I transmembrane proteins that contain three structural domains: a leucine-rich repeats (LRRs) motif, a transmembrane domain, and a cytoplasmic Toll/IL-1 receptor (TIR) domain. The LRRs motif is responsible for pathogen recognition, whereas the TIR domain interacts with signal transduction adaptors and initiates signaling.

    TLR-Toll--Like Receptor Structure - Creative BioMart

    TLRs are single-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Humans lack genes for TLR11, TLR12, and TLR13 and mice lack a functional gene for TLR10. The receptors TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the cell membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles (because they are sensors of nucleic acids).

    TLRs can recognize a wide range of PAMPs derived from bacteria, viruses, fungi, and parasites. Each TLR has specificity for specific PAMPs. For example, TLR2 recognizes bacterial lipoproteins and peptidoglycans, while TLR4 recognizes lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria. TLR3 recognizes viral double-stranded RNA, and TLR9 recognizes unmethylated CpG DNA motifs commonly found in bacterial and viral DNA.

    Table 1 Characteristics of different human TLRs. (Sameer AS, et al., 2021)

    TLR member TLR expression TLR coreceptor Gene & its location Origin TLR active form Signaling adaptors
    TLR1 Cell membrane TLR2 TLR1-6-10
    4p14    		 Nonviral TLR1-TLR2 BCAP, TIRAP, MyD88, SCIMP
    TLR2 Cell membrane TLR1, 2, 6 & 10
    CD14, CD36, integrin, RP105, MBL, LBP    		 TLR2
    4q31.3    		 Nonviral TLR1-TLR2
    TLR2-TLR2
    TLR2-TLR6
    TLR2-TLR10    		 BCAP, TIRAP, MyD88, SCIMP
    TLR3 Endoplasmic reticulum, lysosomal membrane CD14, Mex3B TLR3
    4q35.1    		 Viral TLR3-TLR3 SARM, SCIMP, TRIF, TICAM1
    TLR4 Cell membrane, endoplasmic reticulum, lysosomal membrane MD2, LY96, CD14, CD36, LBP, RP105 TLR4
    9q33.1    		 Nonviral TLR4/MD2-TLR4/MD2
    TLR4-TLR6    		 BCAP, TIRAP, MyD88, SARM, SCIMP, TICAM1, TICAM2
    TLR5 Cell membrane TLR5
    1q41    		 Nonviral TLR5-TLR5 MyD88, TICAM1
    TLR6 Cell membrane TLR2, CD36, LBP TLR1-6-10
    4p14    		 Nonviral TLR2-TLR6
    TLR4-TLR6    		 BCAP, TIRAP, MyD88, SCIMP
    TLR7 Cell membrane, endoplasmic reticulum, lysosomal membrane CD14 TLR7
    Xp22.2    		 Viral TLR7-TLR7 MyD88
    TLR8 Endoplasmic reticulum, lysosomal membrane TLR8
    Xp22.2    		 Viral TLR8-TLR8 MyD88
    TLR9 Endoplasmic reticulum, lysosomal membrane CD14 TLR9
    3p21.2    		 Viral TLR9-TLR9 TIRAP, MyD88, SCIMP
    TLR10 Cell membrane, endoplasmic reticulum, lysosomal membrane TLR1-6-10
    4p14    		 Nonviral TLR1-TLR10
    TLR2-TLR10
    TLR10-TLR10    		 MyD88

    Signaling of Toll-Like Receptors (TLRs)

    Upon ligand binding, TLRs recruit adaptor proteins to their TIR domains, initiating downstream signaling pathways. The main adaptors include MyD88 (myeloid differentiation primary response 88), TRIF (TIR-domain-containing adapter-inducing interferon-β), TRAM (TRIF-related adapter molecule), and TIRAP (TIR domain-containing adaptor protein). These adaptors activate various signaling pathways, such as the NF-κB pathway and the MAPK pathway, leading to the production of pro-inflammatory cytokines, type I interferons, and other immune mediators.

    Dynamics of the toll-like receptor signaling.Fig. 2 Dynamics of the toll-like receptor signaling. (Sameer AS, et al., 2021)

    Available Resources for Toll-Like Receptors (TLRs)

    Creative BioMart offers a wide range of quality tools related to Toll-like receptors, including recombinant proteins and more. At the same time, we provide personalized services according to the specific needs of our customers. In addition, we provide comprehensive resources, including involved pathways, protein functions, interacting proteins, related articles, and other relevant topics, to help advance research related to TLRs.

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    References:

    1. Sameer AS, Nissar S. Toll-Like Receptors (TLRs): Structure, functions, signaling, and role of their polymorphisms in colorectal cancer susceptibility. Biomed Res Int. 2021;2021:1157023. doi:10.1155/2021/1157023
    2. Vijay K. Toll-like receptors in immunity and inflammatory diseases: Past, present, and future. Int Immunopharmacol. 2018;59:391-412. doi:10.1016/j.intimp.2018.03.002
    3. El-Zayat S R, Sibaii H, Mannaa F A. Toll-like receptors activation, signaling, and targeting: an overview[J]. Bulletin of the National Research Centre, 2019, 43(1):187. DOI:10.1186/s42269-019-0227-2.
    4. Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014;5:461. Published 2014 Sep 25. doi:10.3389/fimmu.2014.00461
    5. Kumar H, Kawai T, Akira S. Toll-like receptors and innate immunity. Biochem Biophys Res Commun. 2009;388(4):621-625. doi:10.1016/j.bbrc.2009.08.062