Toll-like receptors

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

TLR; Toll-like receptors

History
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Christiane Nüsslein-Volhard, 1985

Definition
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In evolutionary terms, TLRs are old, conserved PRRs (Pattern Recognition Receptors). Toll-like receptors are primarily used for the recognition of so-called "Pathogen Associated Molecular Patterns" ( PAMPs ). TLRs are transmembrane glycoproteins. Their extracellular, N-terminal domain consists of an LRR that specifically binds different ligands. A transmembrane domain follows. The signal transduction takes place through the cytoplasmic "Toll-interleukin-1 receptor homology" domain, TIR for short, which recruits molecules that also contain a TIR domain, but can differ from TLR to TLR.

In humans, there are now 10 (TLR-1 to 10) and 12 murine (TLR-1 to 9 + 11 and 13). 6 of the human TLRs bind PAMPs extracellularly (TLR-1, 2, 4, 5, 6, 10) while 4 are only localized intracellularly (TLR-3, 7, 8 and 9).

TLRs are expressed by immune cells of the innate and also by cells of the adaptive immune system (B and T cells) as well as by numerous non-immune cells. This wide distribution makes TLRs an excellent tool for both the innate and the acquired immune system. TLRs thus provide an overarching tool for the recognition of pathogens and the activation of antigen-specific acquired immunity. Through the activity of TLRs, the innate defence mechanisms (see below immunity, innate) can distinguish between "self" and "foreign". For the detection of pathogens, the TLRs need different adaptor molecules for the activation of intracellular signalling cascades such as: MyD88, TICAM-1 (TRIF), TIRAP/MAL, TRAM, and SARM.

TLRs also play a supporting role in nickel allergy.

General information
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The key factors "C3a" and "C5a" of the complement system attract macrophages and neutrophil granulocytes. These carry TLR-type receptors on their surface. These have an extracellular (leucine rich repeats. LRR-domain) and an intracellular TIR-domain (Toll-IL-1 receptor homologous domain). The extracellular domain is used for ligand binding, while the intracellular domain is used for signal transduction.

All Toll-like receptors (with the exception of TLR3) have the adapter protein MyD88 (myeloid differentiation primary response gene 88) in common. They associate with IRAK (IL-1 receptor-associated kinase) via this adapter protein. This process leads to the translocation of IRFs and NF-kappa B. TLR3 on the other hand, binds to TRIF (TIR-domain-containing adapter-inducing interferon-beta).

IRFs and NF-kappaB initiate the transcription of proinflammatory cytokines Interleukin-1β, Interleukin-6, Interleukin-12p70, Interleukin-23 and TNF-α as well as of type I interferons (IFN-alpha and interferon-beta).

This leads to phosphorylation and thus activation of intracellular kinases (see below MAP kinases), whose task is the phyosphorylation of intracellular inhibitors of transcription factors. Through phosphorylation, the inhibitor loses its inhibitory effect. It releases its transcription factor; this is translocated into the cell nucleus where it regulates the expression of genes that serve to defend against infection. Imiquimod, for example, is the ligand for TLR7 and TLR8.

Occurrence
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TLRs are found in all vertebrates, but also in simple organisms. TLRs recognise different functional components of viruses, bacteria and fungi and can thus trigger biochemical reaction chains in the cells that serve to defend against these pathogens. TLRs can also detect internal dangers, for example, those that arise from tissue damage. Here, the body's own molecules bind the TLRs. These signal molecules are called DAMP (danger associated molecular pattern).

Note(s)
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The name "Toll-like receptor" is derived from a protein in Drosophila melanogaster called Toll. "Toll" was initially thought to be a gene product that is important for the development of the dorso-ventral axis in Drosophila embryos. Tolllike receptors (TLRs) consist of proteins that are similar to Toll, i.e. "Toll-like".

Literature
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  1. Lemaitre B et al (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86: 973-983
  2. Rad R et al (2007) Toll-like receptor-dependent activation of antigen-presenting cells affects daptive immunity to Helicobacter pylori. Gastroenterology. 133: 150-163
  3. Satoh M et al (2007) Association between toll-like receptor 8 expression and adverse clinical outcomes in patients with enterovirus-associated dilated cardiomyopathy. At Heart J 154: 581-858

Tables
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receptor

Target antigen

TLR1

tri-acetylated lipoproteins

TLR2

various lipoproteins and glycolipids, yeast fungi, protozoa (e.g. Trypanosoma cruzi); mediates the immune response against Mycobacterium tuberculosis, Borrelia burgdorferi and Treponema pallidum, among others

TLR3

long double-stranded RNA (occurs in viruses)

TLR4

Lipopolysaccharide (endotoxin); important for the recognition of Gram-negative bacteria such as Escherichia coli

TLR5/6

Flagellin and bacterial peptidoglycans (occur in gram-pos. and gram-neg. bacteria)

TLR7/8

short single- and double-stranded RNA (ssRNA)

TLR9

CpG-rich DNA

TLR11

E. coli; profilin-like protein from Toxoplasma gondii

TLR10/12

unknown

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Last updated on: 29.10.2020