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Toll-like receptor signalling

Key Points

  • Toll-like receptors (TLRs) have an extracellular region, which contains leucine-rich repeat motifs, and a cytoplasmic tail, which has a Toll/interleukin-1(IL-1) receptor (TIR) domain.

  • Different TLRs recognize different surface and intracellular components of microorganisms.

  • The interaction between a TLR and a microbial component triggers the activation of the innate immune system, as well as the development of acquired immunity.

  • TLR-signalling pathways originate from the TIR domain, as a result of its recruitment of TIR-domain-containing adaptors — such as MyD88 (myeloid differentiation primary-response protein 88), TIRAP (TIR-domain-containing adaptor protein), TRIF (TIR-domain-containing adaptor protein inducing interferon-β) and TRAM (TRIF-related adaptor molecule).

  • Signalling through each TLR requires MyD88 for the production of inflammatory cytokines. However, a MyD88-independent pathway exists, and following signalling through TLR3 or TLR4, it leads to the production of type I interferons.

  • TRIF is essential for the MyD88-independent pathway of TLR3 and TLR4 signalling, as well as for the TLR4-mediated production of inflammatory cytokines.

  • TRAM is involved specifically in the TLR4-mediated, MyD88-independent pathway, whereas TIRAP mediates the TLR2- and TLR4-mediated, MyD88-dependent pathway.

  • The TLR-signalling pathways are negatively regulated by TLR-inducible molecules — such as IRAK-M (IL-1-receptor (IL-1R)-associated kinase M), SOCS1 (suppressor of cytokine signalling 1), MyD88s (MyD88 short), SIGIRR (single immunoglobulin IL-1R-related molecule) and ST2.

Abstract

One of the mechanisms by which the innate immune system senses the invasion of pathogenic microorganisms is through the Toll-like receptors (TLRs), which recognize specific molecular patterns that are present in microbial components. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also instructs the development of antigen-specific acquired immunity. Here, we review the rapid progress that has recently improved our understanding of the molecular mechanisms that mediate TLR signalling.

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Figure 1: TLR structure and signalling.
Figure 2: TLR4 signalling: MyD88-dependent and -independent pathways.
Figure 3: Involvement of TIR-domain-containing adaptors in TLR-signalling pathways.
Figure 4: TRIF-dependent induction of IFN-β.
Figure 5: Negative regulation of TLR signalling.

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Acknowledgements

We thank M. Lamphier for careful appraisal of the manuscript and M. Hashimoto for excellent secretarial assistance. This work was supported by grants from the Special Coordination Funds of the Japanese Ministry of Education, Culture, Sports, Science and Technology, the Uehara Memorial Foundation, Japan, and the Naito Foundation, Japan.

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Correspondence to Shizuo Akira.

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DATABASES

Entrez Gene

AKT

BTK

ECSIT

IFN-β

IκB

IKK-α

IKK-β

IKK-γ

IL-1R

IRAK1

IRAK2

IRAK4

IRAK-M

IRF3

MEKK3

MyD88

pellino-1

pellino-2

pellino-3

PI3K

RIP1

SARM

SIGIRR

SOCS1

ST2

TAB1

TAB2

TAK1

TBK1

TIRAP

TLR1

TLR2

TLR3

Tlr4

TLR5

TLR7

TLR9

TOLLIP

TPL2

TRAF6

TRAM

TRIF

UBC13

Glossary

SMALL INTERFERING RNAS

(siRNAs). Synthetic double-stranded RNA molecules of 19–23 nucleotides, which are used to knockdown (silence the expression of) a specific gene. This is known as RNA interference (RNAi) and is mediated by the sequence-specific degradation of mRNA.

UBIQUITYLATION

The attachment of the small protein ubiquitin to lysine residues present in other proteins. This tags these proteins for rapid cellular degradation.

ENDOTOXIC SHOCK

A serious systemic disorder that leads to multiple organ failure and death. It is caused by an excessive release of lipopolysaccharide (also known as endotoxin) during Gram-negative bacterial infection.

LPS TOLERANCE

A transient state of hyporesponsiveness to subsequent stimulation with lipopolysaccharide (LPS), which is induced by the administration of Toll-like receptor ligands in vivo and in vitro.

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Akira, S., Takeda, K. Toll-like receptor signalling. Nat Rev Immunol 4, 499–511 (2004). https://doi.org/10.1038/nri1391

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