Toll-like receptor

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Toll-like receptor
The curved leucine-rich repeat region of toll-like receptors, represented here by TLR3
Identifiers
SymbolToll-like receptor
Membranome7
PIRSF037595

Toll-like receptors (TLRs) are a class of

TLR11, TLR12, and TLR13. Humans lack genes for TLR11, TLR12 and TLR13[1] and mice lack a functional gene for TLR10.[2] 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).[3]

TLRs received their name from their similarity to the protein coded by the toll gene.[4]

Function

The ability of the immune system to recognize

fibroblasts).[5]

The binding of

molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity.[6][7]

Upon activation, TLRs recruit

CD4+ T cells
. In the case of a viral factor, the infected cell may shut off its protein synthesis and may undergo programmed cell death (apoptosis). Immune cells that have detected a virus may also release anti-viral factors such as interferons.

Toll-like receptors have also been shown to be an important link between innate and adaptive immunity through their presence in dendritic cells.[8] Flagellin, a TLR5 ligand, induces cytokine secretion on interacting with TLR5 on human T cells.[8]

Superfamily

TIR domain from TLR2. This is a signal transduction domain distinct from the LRR domain discussed earlier.
Main article: Toll-interleukin receptor

TLRs are a type of

superfamily
, known as the "interleukin-1 receptor / toll-like receptor superfamily"; all members of this family have in common a so-called TIR (toll-IL-1 receptor) domain.

Three subgroups of TIR domains exist. Proteins with subgroup 1 TIR domains are receptors for

Immunoglobulin (Ig) domains. Proteins with subgroup 2 TIR domains are classical TLRs, and bind directly or indirectly to molecules of microbial origin. A third subgroup of proteins containing TIR domains consists of adaptor proteins that are exclusively cytosolic
and mediate signaling from proteins of subgroups 1 and 2.

Extended family

TLRs are present in

plant pattern recognition receptors are well known to be required for host defence against infection. The TLRs thus appear to be one of the most ancient, conserved components of the immune system
.

In recent years TLRs were identified also in the mammalian nervous system. Members of the TLR family were detected on glia, neurons and on neural progenitor cells in which they regulate cell-fate decision.[10]

It has been estimated that most mammalian species have between ten and fifteen types of toll-like receptors. Thirteen TLRs (named simply TLR1 to TLR13) have been identified in humans and mice together, and equivalent forms of many of these have been found in other mammalian species.

mice, but appears to have been damaged at some point in the past by a retrovirus. On the other hand, mice express TLRs 11, 12, and 13, none of which is represented in humans. Other mammals may express TLRs that are not found in humans. Other non-mammalian species may have TLRs distinct from mammals, as demonstrated by the anti-cell-wall TLR14, which is found in the Takifugu pufferfish.[14]
This may complicate the process of using experimental animals as models of human innate immunity.

Vertebrate TLRs are divided by similarity into the families of TLR 1/2/6/10/14/15, TLR 3, TLR 4, TLR 5, TLR 7/8/9, and TLR 11/12/13/16/21/22/23.[14]

TLRs in Drosophila immunity

The Toll immunity pathway as found in the fruit fly[15][16][17][18]

The involvement of toll signalling in immunity was first demonstrated in the fruit fly,

haemolymph as an inactive dimeric precursor. The toll receptor shares the cytoplasmatic TIR domain with mammalian TLRs, but the ectodomain and intracytoplasmatic tail are different. This difference might reflect a function of these receptors as cytokine receptors rather than PRRs
.

The toll pathway is activated by different stimuli, such as

IκB), phosphorylated Cactus is polyubiquitylated and degraded, allowing nuclear translocation of DIF (dorsal-related immunity factor; a homologue of mammalian NF-κB) and induction of transcription of genes for antimicrobial peptides (AMPs) such as drosomycin.[21]

Drosophila have a total of 9 toll family and 6 spz family genes that interact with each other to differing degrees.[22]

TLR2

Main article:
TLR2

TLR2
has also been designated as CD282 (cluster of differentiation 282).

TLR3

shRNA knockdown of TLR3 or its adaptor protein TRIF. Taken together, stimulation of TLR3 causes great changes in chromatin remodeling and nuclear reprogramming, and activation of inflammatory pathways is required for these changes, induction of pluripotency genes and generation of human induced pluripotent stem cells (iPSC) colonies.[23]

TLR11

As noted above, human cells do not express

E.coli and the apicomplexan parasite Toxoplasma gondii. With Toxoplasma its ligand is the protein profilin and the ligand for E. coli is flagellin. The flagellin from the enteropathogen Salmonella is also recognized by TLR11.[24]

As mouse TLR11 is able to recognize Salmonella effectively, normal mice do not get infected by oral

disease model of human typhoid fever.[25]

Summary of known mammalian TLRs

Toll-like receptors bind and become activated by different ligands, which, in turn, are located on different types of organisms or structures. They also have different adapters to respond to activation and are located sometimes at the cell surface and sometimes to internal

cell types
:

Receptor Ligand(s)[26] Ligand location[26] Adapter(s) Location Cell types[26]
TLR 1
 multiple triacyl lipopeptides Bacterial lipoprotein
MyD88
/MAL		 cell surface
TLR 2
 multiple glycolipids Bacterial peptidoglycans MyD88/MAL cell surface
multiple lipopeptides and proteolipids Bacterial peptidoglycans
lipoteichoic acid Gram-positive bacteria
HSP70
Host cells
zymosan (Beta-glucan) Fungi
Numerous others
TLR 3
poly I:C
 viruses
TRIF
 cell compartment
  • Dendritic cells
  • B lymphocytes
TLR 4
 lipopolysaccharide Gram-negative bacteria MyD88/MAL/
TRIF
/TRAM		 cell surface
several heat shock proteins Bacteria and host cells
fibrinogen host cells
heparan sulfate fragments host cells
hyaluronic acid fragments host cells
nickel[31]
Various opioid drugs
TLR 5
Bacterial flagellin
 Bacteria MyD88 cell surface
  • monocyte/macrophages
  • a subset of dendritic cells
  • Intestinal epithelium
  • Breast cancer cells
  • B lymphocytes
Profilin[32] Toxoplasma gondii
TLR 6
 multiple diacyl lipopeptides Mycoplasma MyD88/MAL cell surface
  • monocytes/macrophages
  • Mast cells
  • B lymphocytes
TLR 7
 imidazoquinoline small synthetic compounds MyD88 cell compartment
loxoribine (a guanosine analogue)
bropirimine
resiquimod
single-stranded RNA RNA viruses
TLR 8
 small synthetic compounds; single-stranded Viral RNA, phagocytized bacterial RNA(24) MyD88 cell compartment
  • monocytes/macrophages
  • a subset of dendritic cells
  • Mast cells
  • Intestinal epithelial cells (IECs) *only in Crohn's or ulcerative colitis
  • hippocampal interneurons [33]
TLR 9
 unmethylated
CpG Oligodeoxynucleotide
DNA		 Bacteria, DNA viruses MyD88 cell compartment
  • monocytes/macrophages
  • Plasmacytoid dendritic cells[28]
  • B lymphocytes
TLR 10
 triacylated lipopeptides[34] unknown cell surface
TLR 11
 Profilin Toxoplasma gondii[38] MyD88 cell compartment[39]
Flagellin Bacteria (E. coli, Salmonella)[24]
TLR 12 Profilin Toxoplasma gondii[40] MyD88 cell compartment
  • Neurons[41]
  • plasmacytoid dendritic cells
  • conventional dendritic cells
  • macrophages
TLR 13[42][43] bacterial ribosomal RNA sequence "CGGAAAGACC" (but not the methylated version)[44] Virus, bacteria MyD88, TAK-1 cell compartment
  • monocytes/macrophages
  • conventional dendritic cells

Ligands

Toll-Like Receptor (TLR) ligands among RNA and DNA viruses, Gram-positive and Gram-negative bacteria, fungi, and protists

Because of the specificity of toll-like receptors (and other innate immune receptors) they cannot easily be changed in the course of evolution, these receptors recognize molecules that are constantly associated with threats (i.e., pathogen or cell stress) and are highly specific to these threats (i.e., cannot be mistaken for self molecules that are normally expressed under physiological conditions). Pathogen-associated molecules that meet this requirement are thought to be critical to the pathogen's function and difficult to change through mutation; they are said to be evolutionarily conserved. Somewhat conserved features in pathogens include

flagella; double-stranded RNA of viruses; or the unmethylated CpG islands of bacterial and viral DNA; and also of the CpG islands found in the promoters of eukaryotic DNA; as well as certain other RNA and DNA molecules. As TLR ligands are present in most pathogens, they may also be present in pathogen-derived vaccines (e.g. MMR, influenza, polio vaccines) most commercially available vaccines have been assessed for their inherent TLR ligands' capacity to activate distinct subsets of immune cells.[45][46] For most of the TLRs, ligand recognition specificity has now been established by gene targeting (also known as "gene knockout"): a technique by which individual genes may be selectively deleted in mice.[47][48]
See the table above for a summary of known TLR ligands.

Endogenous ligands

The stereotypic inflammatory response provoked by toll-like receptor activation has prompted speculation that endogenous activators of toll-like receptors might participate in autoimmune diseases. TLRs have been suspected of binding to host molecules including

blood clotting), heat shock proteins (HSPs), HMGB1, extracellular matrix components and self DNA (it is normally degraded by nucleases, but under inflammatory and autoimmune conditions it can form a complex with endogenous proteins, become resistant to these nucleases and gain access to endosomal TLRs as TLR7 or TLR9). These endogenous ligands are usually produced as a result of non-physiological cell death.[49]

Signaling

Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations.

TLRs are believed to function as

LBP
) are known to facilitate the presentation of LPS to MD-2.

A set of endosomal TLRs comprising TLR3, TLR7, TLR8 and TLR9 recognize

cytokines as well as type I interferons (interferon type I
) to help fight viral infection.

The adapter proteins and kinases that mediate TLR signaling have also been targeted. In addition, random germline mutagenesis with

TRIF, and TRAM (TRIF-related adaptor molecule).[50][51][52]

TLR signaling is divided into two distinct signaling pathways, the MyD88-dependent and TRIF-dependent pathway.

MyD88-dependent pathway

The MyD88-dependent response occurs on dimerization of TLRs, and is used by every TLR except TLR3. Its primary effect is activation of NFκB and

TIR family. MyD88 then recruits IRAK4, IRAK1 and IRAK2. IRAK kinases then phosphorylate and activate the protein TRAF6, which in turn polyubiquinates the protein TAK1, as well as itself to facilitate binding to IKK-β. On binding, TAK1 phosphorylates IKK-β, which then phosphorylates IκB causing its degradation and allowing NFκB to diffuse into the cell nucleus and activate transcription and consequent induction of inflammatory cytokines.[49]

TRIF-dependent pathway

Both TLR3 and TLR4 use the TRIF-dependent pathway, which is triggered by

TRIF. TRIF activates the kinases TBK1 and RIPK1, which creates a branch in the signaling pathway. The TRIF/TBK1 signaling complex phosphorylates IRF3 allowing its translocation into the nucleus and production of Interferon type I. Meanwhile, activation of RIPK1 causes the polyubiquitination and activation of TAK1 and NFκB transcription in the same manner as the MyD88-dependent pathway.[49]

TLR signaling ultimately leads to the induction or suppression of genes that orchestrate the inflammatory response. In all, thousands of genes are activated by TLR signaling, and collectively, the TLRs constitute one of the most

pleiotropic
yet tightly regulated gateways for gene modulation.

TLR4 is the only TLR that uses all four adaptors. Complex consisting of TLR4, MD2 and LPS recruits TIR domain-containing adaptors TIRAP and MyD88 and thus initiates activation of NFκB (early phase) and MAPK. TLR4-MD2-LPS complex then undergoes endocytosis and in endosome it forms a signalling complex with TRAM and TRIF adaptors. This TRIF-dependent pathway again leads to IRF3 activation and production of type I interferons, but it also activates late-phase NFκB activation. Both late and early phase activation of NFκB is required for production of inflammatory cytokines.[49]

Medical relevance

Imiquimod (cardinally used in dermatology) is a TLR7 agonist, and its successor resiquimod, is a TLR7 and TLR8 agonist.[53] Recently, resiquimod has been explored as an agent for cancer immunotherapy,[54] acting through stimulation of tumor-associated macrophages.

Several TLR ligands are in clinical development or being tested in animal models as vaccine adjuvants,[55] with the first clinical use in humans in a recombinant herpes zoster vaccine in 2017, which contains a monophosphoryl lipid A component.

TLR7 messenger RNA expression levels in dairy animals in a natural outbreak of foot-and-mouth disease have been reported.[56]

respiratory depression and hyperalgesia.[61] Drugs that block the action of TNF-α or IL-1β have been shown to increase the analgesic effects of opioids and reduce the development of tolerance and other side-effects,[62][63]
and this has also been demonstrated with drugs that block TLR4 itself.

The "unnatural" enantiomers of opioid drugs such as (+)-morphine and (+)-naloxone lack affinity for opioid receptors, still produce the same activity at TLR4 as their "normal" enantiomers.[64][65] So, "unnatural" entianomers of opioids such as (+)-naloxone, can be used to block the TLR4 activity of opioid analgesic drugs without having any affinity for μ-opioid receptor[66][65][67]

Discovery

When microbes were first recognized as the cause of infectious diseases, it was immediately clear that multicellular organisms must be capable of recognizing them when infected and, hence, capable of recognizing molecules unique to microbes. A large body of literature, spanning most of the last century, attests to the search for the key molecules and their receptors. More than 100 years ago,

endotoxin" to describe a substance produced by Gram-negative bacteria that could provoke fever and shock in experimental animals. In the decades that followed, endotoxin was chemically characterized and identified as a lipopolysaccharide (LPS) produced by most Gram-negative bacteria. This lipopolysaccharide is an integral part of the gram-negative membrane and is released upon destruction of the bacterium. Other molecules (bacterial lipopeptides, flagellin, and unmethylated DNA) were shown in turn to provoke host responses that are normally protective. However, these responses can be detrimental if they are excessively prolonged or intense. It followed logically that there must be receptors for such molecules, capable of alerting the host to the presence of infection, but these remained elusive for many years. Toll-like receptors are now counted among the key molecules that alert the immune system
to the presence of microbial infections.

The prototypic member of the family, the toll receptor (P08953; Tl) in the fruit fly

fungal infection, which it achieved by activating the synthesis of antimicrobial peptides.[19]

The first reported human toll-like receptor was described by Nomura and colleagues in 1994,

interleukin-1 (IL-1) receptor, also had homology to drosophila toll; the cytoplasmic portions of both molecules were similar.[71]

In 1997,

positional cloning
to prove that mice that could not respond to LPS had mutations that abolished the function of TLR4. This identified TLR4 as one of the key components of the receptor for LPS.

The history of Toll-like receptors

In turn, the other TLR genes were ablated in mice by gene targeting, largely in the laboratory of Shizuo Akira and colleagues. Each TLR is now believed to detect a discrete collection of molecules – some of microbial origin, and some products of cell damage – and to signal the presence of infections.[73]

Plant homologs of toll were discovered by Pamela Ronald in 1995 (rice XA21)[74] and Thomas Boller in 2000 (Arabidopsis FLS2).[75]

In 2011, Beutler and Hoffmann were awarded the Nobel Prize in Medicine or Physiology for their work.[76] Hoffmann and Akira received the Canada Gairdner International Award in 2011.[77]

Notes and references

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See also

External links

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