Toll-like receptor

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The curved leucine-rich repeat region of Toll-like receptors, represented here by TLR3

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors usually expressed in sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have breached 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.

They receive their name from their similarity to the protein coded by the toll gene identified in Drosophila in 1985 by Christiane Nüsslein-Volhard.[1] The researchers were so surprised that they spontaneously shouted out in German, "Das ist ja toll!" which translates as "That's great!"[2]

Diversity[edit]

TLRs are a type of pattern recognition receptor (PRR) and recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). TLRs together with the Interleukin-1 receptors form a receptor 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 interleukins that are produced by macrophages, monocytes, and dendritic cells and all have extracellular 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.

TLRs are present in vertebrates, as well as in invertebrates. Molecular building blocks of the TLRs are represented in bacteria and in plants, and 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.[3]

Discovery[edit]

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, Richard Pfeiffer, a student of Robert Koch, coined the term "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. They are named for their similarity to toll, a receptor first identified in the fruit fly Drosophila melanogaster, and originally known for its developmental function in that organism. In 1996, toll was found by Jules A. Hoffmann and his colleagues to have an essential role in the fly's immunity to fungal infection,[4] which it achieved by activating the synthesis of antimicrobial peptides. The plant homologs were discovered by Pamela Ronald in 1995 (rice XA21)[5] and Thomas Boller in 2000 (Arabidopsis FLS2).[6]

The first reported human toll-like receptor was described by Nomura and colleagues in 1994,[7] mapped to a chromosome by Taguchi and colleagues in 1996.[8] Because the immune function of toll in Drosophila was not then known, it was assumed that TIL (now known as TLR1) might participate in mammalian development. However, in 1991 (prior to the discovery of TIL) it was observed that a molecule with a clear role in immune function in mammals, the interleukin-1 (IL-1) receptor, also had homology to drosophila toll; the cytoplasmic portions of both molecules were similar.[9]

In 1997, Charles Janeway and Ruslan Medzhitov showed that a toll-like receptor now known as TLR4 could, when artificially ligated using antibodies, induce the activation of certain genes necessary for initiating an adaptive immune response.[10] TLR 4 function as an LPS sensing receptor was discovered by Bruce A. Beutler and colleagues.[11] These workers used 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.

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.

On October 3, 2011, Dr. Beutler and Dr. Hoffmann were awarded the Nobel Prize in Medicine or Physiology for their work.[12] Drs. Hoffmann and Akira received the Canada Gairdner International Award in 2011.[13]

Extended family[edit]

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.[14][15][16] However, equivalents of certain TLR found in humans are not present in all mammals. For example, a gene coding for a protein analogous to TLR10 in humans is present in 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 TLR14, which is found in the Takifugu pufferfish.[17] This may complicate the process of using experimental animals as models of human innate immunity.

TLRs in Drosophila immunity[edit]

Drosophila melanogaster has only innate immune responses. Response to fungal or bacterial infection occurs through two distinct signalling cascades, one of which is toll pathway and the other is immune deficiency (IMD) pathway. The toll pathway is similar to mammalian TLR signalling, but unlike mammalian TLRs, toll is not activated directly by PAMPs. Its receptor ectodomain recognizes cleaved form of the cytokine Spätzle, which is secreted in the haemolymph as inactive dimeric precursor. Toll receptor shares the cytoplasmatic TIR domain with mammalian TLRs, but ectodomain and intracytoplasmatic tail are different. This difference might reflect a function of these receptors as cytokine receptors rather than PRRs. Toll pathway is activated by different stimuli, such as Gram positive bacteria, fungi and virulence factors. First, the Spätzle processing enzyme (SPE) is activated in response to infection and cleaves Spätzle. Cleaved Spätzle then binds to toll receptor and crosslinks its ectodomains. This triggers conformational changes in receptor resulting in signalling through toll. Signalling now is very similar to mammalian signalling through TLRs. Toll-induced signalling complex (TICS) is formed, comprising MyD88, Tube and Pelle( the orthologue of mammalian IRAK). Signal from TICS is then transduced to Cactus (homologue of mammalian IκB), phosphorylated Cactus is polyubiquitylated and degraded, allowing nuclear translocation of DIF (dorsal-related immunity facor; a homologue of mammalian NF-κB) and induction of transcription of genes for antimicrobial peptides (AMPs) such as Drosomycin.[18]

TLR2[edit]

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

TLR3[edit]

TLR3 is the only toll-like receptor which does not use the MyD88 dependent pathway. Its ligand is retroviral double-stranded RNA (dsRNA), which activates the TRIF dependent signalling pathway. To explore the role of this pathway in retroviral reprograming, knock down techniques of TLR3 or TRIF were prepared, and results showed that only the TLR3 pathway is required for full induction of target gene expression by the retrovirus expression vector. This retroviral expression of four transcriptional factors (Oct4, Sox2, Klf4 and c-Myc; OSKM) induces pluripotency in somatic cells. This is supported by study, which shows, that efficiency and amount of human iPSC generation, using retroviral vectors, is reduced by knockdown of the pathway with peptide inhibitors or 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.[19]

TLR11[edit]

As mentioned above, human cells do not express TLR11, but mice do. It has been characterized, that mouse-specific TLR11 recognizes uropathogenic E.coli and apicomplexan parasite Toxoplasma gondii. It’s ligand is profilin protein in case of Toxoplasma, but ligand for E. coli is still not known. Recently there was found another enteropathogen which ligand is bound by TLR11. It is Salmonella spp. This gram-negative flagellated bacteria causes food- and waterborne gastroenteritis and typhoid fever in humans. TLR11 in mouse intestine recognizes this flagellin which causes dimerization of the receptor, activation of NF-κB and production of inflammatory cytokines. TLR11 deficient mice (Knockout mouse) are efficiently infected with orally administered Salmonella Typhi. S. Typhi does not normally infect mice, it is human obligatory pathogen that causes typhoid fever, which affects more than 20 million people and causes more than 220 thousand deaths per year. Because of this, studies were carried out and it was found that tlr-/- mice can be immunized against S. Typhi and they are used as an animal model for studying immune responses against this pathogen and for the development of vaccines, that could be possibly used in the future.[20]

Ligands[edit]

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 bacterial cell-surface lipopolysaccharides (LPS), lipoproteins, lipopeptides, and lipoarabinomannan; proteins such as flagellin from bacterial 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. 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.[21][22] See the table below for a summary of known TLR ligands.

Endogenous ligands[edit]

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 fibrinogen (involved in 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.[23]

Signaling[edit]

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

TLRs are believed to function as dimers. Though most TLRs appear to function as homodimers, TLR2 forms heterodimers with TLR1 or TLR6, each dimer having a different ligand specificity. TLRs may also depend on other co-receptors for full ligand sensitivity, such as in the case of TLR4's recognition of LPS, which requires MD-2. CD14 and LPS-Binding Protein (LBP) are known to facilitate the presentation of LPS to MD-2.

A set of endosomal TLRs comprising TLR3, TLR7, TLR8 and TLR9 recognize nucleic acid derived from viruses as well as endogenous nucleic acids in context of pathogenic events. Activation of these receptor leads to production of inflammatory cytokines as well as type I interferons (interferon type I) to help fighting viral infection.

The adapter proteins and kinases that mediate TLR signaling have also been targeted. In addition, random germline mutagenesis with ENU has been used to decipher the TLR signaling pathways. When activated, TLRs recruit adapter molecules within the cytoplasm of cells in order to propagate a signal. Four adapter molecules are known to be involved in signaling. These proteins are known as MyD88, Tirap (also called Mal), Trif, and Tram (toll-like receptor 4 adaptor protein).[24][25][26]

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

MyD88-dependent pathway[edit]

The MyD88-dependent response occurs on dimerization of the TLR receptor, and is utilized by every TLR except TLR3. Its primary effect is activation of NFκB and Mitogen-activated protein kinase. Ligand binding and conformational change that occurs in the receptor recruits the adaptor protein MyD88, a member of the TIR family. MyD88 then recruits IRAK 4, IRAK1 and IRAK2. IRAK kinases then phosphorylate and activate the protein TRAF6, which in turn polyubiquinates the protein TAK1, as well as itself in order 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.[23]

TRIF-dependent pathway[edit]

Both TLR3 and TLR4 utilize the TRIF-dependent pathway, which is triggered by dsRNA and LPS, respectively. For TLR3, dsRNA leads to activation of the receptor, recruiting the adaptor 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.[23]

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 acivation of NFκB is required for production of inflammatory cytokines.[23]

Summary of known mammalian TLRs[edit]

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 compartments. Furthermore, they are expressed by different types of leucocytes or other cell types:

Receptor Ligand(s)[27] Ligand location[27] Adapter(s) Location Cell types[27]
TLR 1 multiple triacyl lipopeptides Bacteria MyD88/MAL cell surface
TLR 2 multiple glycolipids Bacteria MyD88/MAL cell surface
multiple lipopeptides Bacteria
multiple lipoproteins Bacteria
lipoteichoic acid Gram-positive bacteria
HSP70 Host cells
zymosan (Beta-glucan) Fungi
Numerous others
TLR 3 double-stranded RNA, 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
Various opioid drugs
TLR 5 flagellin Bacteria rowspan=2| MyD88 cell surface
  • monocyte/macrophages
  • a subset of dendritic cells
  • Intestinal epithelium
[[profilin[31]]] 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
single-stranded RNA RNA viruses
TLR 8 small synthetic compounds; single-stranded RNA MyD88 cell compartment
  • monocytes/macrophages
  • a subset of dendritic cells
  • Mast cells
TLR 9 unmethylated CpG Oligodeoxynucleotide DNA Bacteria, DNA viruses MyD88 cell compartment
  • monocytes/macrophages
  • Plasmacytoid dendritic cells[29]
  • B lymphocytes
TLR 10 unknown unknown  ?
TLR 11 Profilin Toxoplasma gondii[32] MyD88 cell compartment[33]
TLR 12 Profilin Toxoplasma gondii[34] MyD88
  • Neurons[35]
  • plasmacytoid dendritic cells
  • conventional dendritic cells
  • macrophages
TLR 13 [36][37] bacterial ribosomal RNA sequence “CGGAAAGACC” Virus, bacteria MyD88, TAK-1 cell compartment
  • monocytes/macrophages
  • conventional dendritic cells

Activation and effects[edit]

Following activation by ligands of microbial origin, several reactions are possible. Immune cells can produce signalling factors called cytokines, which trigger inflammation. In the case of a bacterial factor, the pathogen might be phagocytosed and digested, and its antigens presented to 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.

The discovery of the toll-like receptors finally identified the innate immune receptors that are responsible for many of the innate immune functions that had been studied for many years. It is interesting to note that TLRs seem to be involved only in the cytokine production and cellular activation in response to microbes, and do not play a significant role in the adhesion and phagocytosis of microorganisms.

Schmidt et al. demonstrated that TLR4 is involved in the development of contact allergy to nickel in humans.[38] By binding to two non-conserved histidines, H456 and H458, Ni2+ cross-links the two receptor monomers, TLR4, and MD2, triggering formation of a dimer that structurally resembles the one induced by Lipopolysaccharide. That, in turn, activates the proinflammatory intracellular signal transduction cascades.

Said et al. showed that TLR ligands cause an IL-10-dependent inhibition of CD4 T-cell expansion and function by up-regulating PD-1 levels on monocytes, which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.[39]

Toll-like receptors have also been shown to be an important link between innate and adaptive immunity through their presence in dendritic cells. The TLRs 3 and 4 are present on the surface of monocyte derived dendritic cells and use the Myd88-dependent pathway to produce interleukins 12 and 18 which signal naive T-cells to mature into type 1 helper T cells. These TLRs also use the TRIF pathway to upregulate costimulatory proteins which aid in the differentiation of T-cells. TLRs 7 and 9 are present on the endosome of plasmacytoid dendritic cells. These proteins solely make use of the Myd88 dependent pathway to produce interleukins for the maturation of naive T-cells to type 1 helper T-cells.

Evelyn A. Kurt-Jones et al. also demonstrated TLR4s role in the innate immune response to the respiratory syncytial virus. Cytokine production increased upon exposing human monocytes to RSV. After knocking out CD14, TLR4's coactivator, this response was significantly diminished, as were the responses in C3H/HeJ mice, a mouse strain with reduced immune responses, and mice deficient in TLR4.

Drugs interactions[edit]

Imiquimod (cardinally used in dermatology), and its successor resiquimod, are ligands for TLR7 and TLR8.[40]

The lipid A analogon eritoran acts as a TLR4 antagonist. As of December 2009, it is being developed as a drug against severe sepsis.[41]

Notes and references[edit]

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