Figure 1. Toll-like receptor signaling pathway
What is Toll-like receptor?
Toll-like receptors (TLRs) are a class of proteins that play a key role in innate immunity. They are single domain trans-membrane receptors belong to pattern recognition receptors (PRRs) which usually expressed in sentinel cells such as macrophages dendritic cells and many other non-immune cells such as fibroblasts and epithelial cells. They recognize structurally conserved molecules derived from microbes which are called pathogen-associated molecular patterns (PAMPs) or self-derived molecules derived from damaged cells, referred as damage associated molecules patterns (DAMPs). PAMPs include various bacterial cell wall components such as lipopolysaccharide (LPS), peptidoglycan (PGN) and lipopeptides, as well as flagellin, bacterial DNA and viral double-stranded RNA. DAMPs include intracellular proteins such as heat shock proteins as well as protein fragments from the extracellular matrix. PRRs activate downstream signaling pathways that lead to the induction of innate immune responses by producing inflammatory cytokines, type I interferon (IFN), and other mediators. These processes not only trigger immediate host defensive responses such as inflammation, but also prime and orchestrate antigen-specific adaptive immune responses. These responses are essential for the clearance of infecting microbes as well as crucial for the consequent instruction of antigen-specific adaptive immune responses.
Figure 2. The schematic diagram of the TLRs molecular structure.
Toll-like receptor family
The TLR family comprises 10 members (TLR1–TLR10) in human and 12 (TLR1–TLR9, TLR11–TLR13) in mouse. TLRs localize to the cell surface or to intracellular compartments such as the ER, endosome and lysosome. Cell surface TLRs include TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10, whereas intracellular TLRs are localized in the endosome and include TLR3, TLR7, TLR8, TLR9, TLR11, TLR12, and TLR13 (Figure 1). Cell surface TLRs mainly recognize microbial membrane components such as lipids, lipoproteins, and proteins. Intracellular TLRs recognize nucleic acids derived from bacteria and viruses, and also recognize self-nucleic acids in disease conditions such as autoimmunity.
The function of Toll-like receptor usually based on a dimerization process of two TLR molecules, but not always. For example, TLR-1 and TLR-2 will bind to each other to form a dimmer when recognize PAMPs molecules mainly including lipoproteins, peptidoglycans, lipotechoic acids (LTA, Gram-), zymosan, mannan, and tGPI-mucin. TLR-2 can also form a dimmer with TLR-6 when they recognize the same PAMPs listed above. TLR-4 can recognize lipopolysaccharide (LPS, Gram+) and form a homodimer with another TLR-4 molecule. TLR-5 can recognize bacterial flagellin, but they don’t form a dimmer. TLR-11 is functional in mice and mainly recognize uropathogenic bacterial. TLR-3, 7, 8, 9, 13 are expressed on the endosome surface in the cytoplasm. TLR3 recognizes viral double-stranded RNA (dsRNA), small interfering RNAs, and self-RNAs derived from damaged cells. TLR-7 is predominantly expressed in plasmacytoid DCs (pDCs) and recognizes single-stranded (ss) RNA from viruses. It also recognizes RNA from streptococcus B bacteria in conventional DCs (cDCs). TLR8 responds to viral and bacterial RNA. TLR-9 recognizes bacterial and viral DNA that is rich in unmethylated CpG-DNA motifs. TLR13 recognizes bacterial 23S rRNA and unknown components of vesicular stomatitis virus.
Although there are so many types of TLR molecule which recognize wide range of ligands, all these TLRs share a common structural framework in their extracellular, ligand-binding domains. These domains all adopt horseshoe-shaped structures built from leucine-rich repeat motifs. Typically, on ligand binding, two extracellular domains form an ‘‘m’’-shaped dimer sandwiching the ligand molecule bringing the transmembrane and cytoplasmic domains in close proximity and triggering a downstream signaling cascade (Figure 2).
Toll-like receptor signaling pathway
Toll-like receptor signaling cascade
Relationship with diseases
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