Toll-like receptor
Encyclopedia
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s that play a key role in the innate immune system
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...
. They are single, membrane-spanning, non-catalytic receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses.
They receive their name from their similarity to the protein coded by the Toll
Toll (gene)
The Toll genes encode members of the Toll-like receptor class of proteins. "Toll" is German for "amazing" or "great". Mutants in the Toll gene were originally identified by 1995 Nobel Laureates Christiane Nüsslein-Volhard and Eric Wieschaus and colleagues in the fruit fly Drosophila melanogaster...
gene identified in Drosophila
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
in 1985 by Christiane Nüsslein-Volhard
Christiane Nüsslein-Volhard
Christiane Nüsslein-Volhard is a German biologist who won the Albert Lasker Award for Basic Medical Research in 1991 and the Nobel Prize in Physiology or Medicine in 1995, together with Eric Wieschaus and Edward B...
. The gene in question, when mutated, makes the Drosophila flies look unusual, or 'weird'. The researchers were so surprised that they spontaneously shouted out in German "Das ist ja toll!" which translates as "That's great!".
Diversity
TLRs are a type of pattern recognition receptorPattern recognition receptor
Pattern recognition receptors are a primitive part of the immune system. They are proteins expressed by cells of the innate immune system to identify pathogen-associated molecular patterns , which are associated with microbial pathogens or cellular stress, as well as damage-associated molecular...
(PRR) and recognize molecules that are broadly shared by pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s but distinguishable from host molecules, collectively referred to as pathogen-associated molecular pattern
Pathogen-associated molecular pattern
Pathogen-associated molecular patterns, or PAMPs, are molecules associated with groups of pathogens, that are recognized by cells of the innate immune system. These molecules can be referred to as small molecular motifs conserved within a class of microbes...
s (PAMPs). TLRs together with the Interleukin-1 receptor
Interleukin-1 receptor
Interleukin-1 receptor is a cytokine receptor which binds interleukin 1. Two forms of the receptor exist. The type I receptor is primarily responsible for transmitting the inflammatory effects of interleukin-1 while type II receptors may act as a suppressor of IL-1 activity by competing for...
s 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 macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s, monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
s, and dendritic cell
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
s 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 protein
Adaptor protein
Signal transducing adaptor proteins are proteins which are accessory to main proteins in a signal transduction pathway. These proteins tend to lack any intrinsic enzymatic activity themselves but instead mediate specific protein–protein interactions that drive the formation of protein complexes...
s that are exclusively cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
ic and mediate signaling from proteins of subgroups 1 and 2.
TLRs are present in vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
s, as well as in invertebrate
Invertebrate
An invertebrate is an animal without a backbone. The group includes 97% of all animal species – all animals except those in the chordate subphylum Vertebrata .Invertebrates form a paraphyletic group...
s. 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
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
.
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.
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, Richard Pfeiffer, a student of Robert KochRobert Koch
Heinrich Hermann Robert Koch was a German physician. He became famous for isolating Bacillus anthracis , the Tuberculosis bacillus and the Vibrio cholerae and for his development of Koch's postulates....
, coined the term "endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
" to describe a substance produced by Gram-negative bacteria that could provoke fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
and shock in experimental animal
Model organism
A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. Model organisms are in vivo models and are widely used to...
s. In the decades that followed, endotoxin was chemically characterized and identified as a lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
(LPS) produced by most Gram-negative bacteria. Other molecules (bacterial lipopeptide
Lipopeptide
A lipopeptide is a molecule consisting of a lipid connected to a peptide. Bacteria express these molecules. They are bound by TLR 1, and other, Toll-like receptors.Certain lipopeptides are used as antibiotics....
s, flagellin
Flagellin
Flagellin is a protein that arranges itself in a hollow cylinder to form the filament in bacterial flagellum. It has a mass of about 30,000 to 60,000 daltons...
, and unmethylated DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
) 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
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
to the presence of microbial infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s. They are named for their similarity to Toll
Toll (gene)
The Toll genes encode members of the Toll-like receptor class of proteins. "Toll" is German for "amazing" or "great". Mutants in the Toll gene were originally identified by 1995 Nobel Laureates Christiane Nüsslein-Volhard and Eric Wieschaus and colleagues in the fruit fly Drosophila melanogaster...
, a receptor first identified in the fruit fly Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
, and originally known for its developmental function in that organism. In 1996, Toll was found by Jules A. Hoffmann
Jules A. Hoffmann
Jules A. Hoffmann is a Luxembourgish-born French biologist. He is a research director and member of the board of administrators of the National Center of Scientific Research in Strasbourg, France. In 2007, he became President of the French Academy of Sciences...
and his colleagues to have an essential role in the fly's immunity to fungal infection, which it achieved by activating the synthesis of antimicrobial peptides.
The first reported human Toll-like receptor was described by Nomura and colleagues in 1994, mapped to a chromosome by Taguchi and colleagues in 1996. 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
IL-1
IL-1 may refer to:* Interleukin 1, a protein* Illinois' 1st congressional district* Illinois Route 1* Building 1 of Infinite Loop , the Headquarters of Apple Inc....
) receptor, also had homology to drosophila Toll; the cytoplasmic portions of both molecules were similar.
In 1997, Charles Janeway
Charles Janeway
Charles Alderson Janeway, Jr. was a noted immunologist. A member of the National Academy of Sciences, he held a faculty position at Yale University's Medical School and was an HHMI Investigator....
and Ruslan Medzhitov
Ruslan Medzhitov
Ruslan M. Medzhitov, Ph.D., the David W. Wallace Professor of Immunobiology at Yale School of Medicine, a member of Yale Cancer Center and a Howard Hughes Medical Institute investigator...
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. TLR 4 function as an LPS sensing receptor was discovered by Bruce A. Beutler
Bruce A. Beutler
Bruce Alan Beutler is an American immunologist and geneticist. Together with Jules A. Hoffmann, they received one-half of the 2011 Nobel Prize in Physiology or Medicine, for "their discoveries concerning the activation of innate immunity" Bruce Alan Beutler (born December 29, 1957) is an American...
and colleagues. 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. On October 3, 2011, Dr. Beutler and Dr. Hoffmann were awarded the Nobel Prize in Medicine or Physiology for their work.
In turn, the other TLR genes were ablated in mice by gene targeting, largely in the laboratory of Shizuo Akira
Shizuo Akira
, M.D., Ph.D., is a distinguished and highly cited professor at the Department of Host Defense, Osaka University, Japan...
and colleagues. Each TLR is now believed to detect a discrete collection of molecules of microbial origin, and to signal the presence of infections.
For their work in this area as outlined above, Drs. Hoffmann and Akira received the Canada Gairdner International Award in 2011
Extended family
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. 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 retrovirusRetrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
. 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
Takifugu
Takifugu is a genus of pufferfish, often better known by the Japanese name . There are 25 species belonging to the genus Takifugu, which can be found worldwide from about 45° latitude north to 45° latitude south, mostly in salt water. Their diet consists mostly of algae, molluscs, invertebrates...
pufferfish. This may complicate the process of using experimental animals as models of human innate immunity.
Ligands
Because 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). Pathogen-associated molecules that meet this requirement are usually critical to the pathogen's function and cannot be eliminated or changed through mutation; they are said to be evolutionarily conserved. Well-conserved features in pathogens include bacterial cell-surface lipopolysaccharideLipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
s (LPS), lipoprotein
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
s, lipopeptides, and lipoarabinomannan
Lipoarabinomannan
Lipoarabinomannan, also called LAM, is a glycolipid, and a virulence factor associated with Mycobacterium tuberculosis, the bacteria responsible for tuberculosis. Its primary function is to inactivate macrophages and scavenge oxidative radicals....
; proteins such as flagellin
Flagellin
Flagellin is a protein that arranges itself in a hollow cylinder to form the filament in bacterial flagellum. It has a mass of about 30,000 to 60,000 daltons...
from bacterial flagella; double-stranded RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
of virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es; or the unmethylated CpG
CpG site
CpG sites or CG sites are regions of DNA where a cytosine nucleotide occurs next to a guanine nucleotide in the linear sequence of bases along its length. "CpG" is shorthand for "—C—phosphate—G—", that is, cytosine and guanine separated by only one phosphate; phosphate links any two nucleosides...
islands of bacterial and viral DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
; and certain other RNA and DNA. For most of the TLRs, ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
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. See the table below for a summary of known TLR ligands.
Endogenous ligands
The stereotypic inflammatory response provoked by TLR activation has prompted speculation that endogenous activators of TLRs might participate in autoimmune diseases. TLRs have been suspected of binding to host molecules including fibrinogenFibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
(involved in blood clotting) and heat shock protein
Heat shock protein
Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated...
s (HSPs) and host DNA.
Signaling
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
. Though most TLRs appear to function as homodimers, TLR2 forms heterodimers with TLR1 or TLR6, each dimer having a different ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
specificity. TLRs may also depend on other co-receptors for full ligand sensitivity, such as in the case of TLR4's recognition of LPS
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
, which requires MD-2. CD14
CD14
Cluster of differentiation 14 also known as CD14 is a human gene.The protein encoded by this gene is a component of the innate immune system. CD14 exists in two forms. Either it is anchored into the membrane by a glycosylphosphatidylinositol tail or it appears in a soluble form...
and LPS-Binding Protein (LBP
Lipopolysaccharide-binding protein
Lipopolysaccharide-binding protein is a protein that in humans is encoded by the LBP gene.LBP is a soluble acute-phase protein that binds to bacterial lipopolysaccharide to elicit immune responses by presenting the LPS to important cell surface pattern recognition receptors called CD14 and...
) are known to facilitate the presentation of LPS to MD-2.
The adapter proteins and kinases that mediate TLR signaling have also been targeted. In addition, random germline mutagenesis with ENU
ENU
ENU, also known as N-ethyl-N-nitrosourea , is a highly potent mutagen. For a given gene in mice, ENU can induce 1 new mutation in every 700 loci. It is also toxic at high doses....
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
Myd88
Myeloid differentiation primary response gene is a protein that, in humans, is encoded by the MYD88 gene.-Function:In mice, MyD88 is a universal adapter protein as it is used by all TLRs to activate the transcription factor NF-κB. Mal is necessary to recruit Myd88 to TLR 2 and TLR 4, and MyD88...
, Tirap
TIRAP
TIRAP is an adapter molecule associated with toll-like receptors....
(also called Mal), Trif
Trif
TIR-domain-containing adapter-inducing interferon-β is an adapter in responding to activation of toll-like receptors . It mediates the rather delayed cascade of two TLR-associated signaling cascades, where the other one is dependent upon a MyD88 adapter.Toll-like receptors recognize specific...
, and Tram
Tram
A tram is a passenger rail vehicle which runs on tracks along public urban streets and also sometimes on separate rights of way. It may also run between cities and/or towns , and/or partially grade separated even in the cities...
. The adapters activate other molecules within the cell, including certain protein kinases (IRAK1
IRAK1
Interleukin-1 receptor-associated kinase 1 is an enzyme that in humans is encoded by the IRAK1 gene.-Interactions:IRAK1 has been shown to interact with Myd88, IKBKG, IKK2, TRAF6, CHUK and Ubiquitin C.-Further reading:...
, IRAK4, TBK1, and IKKi
Ikki
The term Ikki can refer to:*In Japanese history, leagues of samurai, farmers, and clergy who engaged in common defense against shogunal forces and greater lords, initiating large and destructive agrarian uprisings. The uprisings were also called ikki...
) that amplify the signal, and ultimately lead 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.
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 compartments. Furthermore, they are expressed by different types of leucocytes or other cell types:| Receptor | Ligand(s) | Ligand location | Adapter(s) | Location | Cell types |
|---|---|---|---|---|---|
| TLR 1 TLR 1 TLR 1 is a member of the Toll-like receptor family of pattern recognition receptors of the innate immune system. TLR1 recognizes pathogen-associated molecular pattern with a specificity for gram-positive bacteria... |
multiple triacyl lipopeptide Lipopeptide A lipopeptide is a molecule consisting of a lipid connected to a peptide. Bacteria express these molecules. They are bound by TLR 1, and other, Toll-like receptors.Certain lipopeptides are used as antibiotics.... s |
Bacteria | MyD88 Myd88 Myeloid differentiation primary response gene is a protein that, in humans, is encoded by the MYD88 gene.-Function:In mice, MyD88 is a universal adapter protein as it is used by all TLRs to activate the transcription factor NF-κB. Mal is necessary to recruit Myd88 to TLR 2 and TLR 4, and MyD88... /MAL |
cell surface |
|
| TLR 2 TLR 2 Toll-like receptor 2 also known as TLR-2 is a protein that in humans is encoded by the TLR2 gene. TLR2 has also been designated as CD282 . TLR-2 plays a role in the immune system... |
multiple glycolipid Glycolipid Glycolipids are lipids with a carbohydrate attached. Their role is to provide energy and also serve as markers for cellular recognition.-Metabolism:... s |
Bacteria | MyD88/MAL | cell surface |
|
| multiple lipopeptides | Bacteria | ||||
| multiple lipoprotein Lipoprotein A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins... s |
Bacteria | ||||
| lipoteichoic acid Lipoteichoic acid Lipoteichoic acid is a major constituent of the cell wall of Gram-positive bacteria. These organisms have an inner membrane and, external to it, a thick peptidoglycan layer. It consists of teichoic acids, long chains of ribitol phosphate and is anchored to the lipid bilayer via a glyceride... |
Bacteria | ||||
| HSP70 Hsp70 The 70 kilodalton heat shock proteins are a family of ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms... |
Host cells | ||||
| zymosan Zymosan Zymosan is a glucan with repeating glucose units connected by β-1,3-glycosidic linkages. It binds to TLR 2.Zymosan is prepared from yeast cell wall and consists of protein-carbohydrate complexes. It is used to induce experimental sterile inflammation... (Beta-glucan Beta-glucan β-Glucans are polysaccharides of D-glucose monomers linked by β-glycosidic bonds. β-glucans are a diverse group of molecules that can vary with respect to molecular mass, solubility, viscosity, and three-dimensional configuration... ) |
Fungi | ||||
| Numerous others | |||||
| TLR 3 TLR 3 Toll-like receptor 3 also known as CD283 is a protein that in humans is encoded by the TLR3 gene... |
double-stranded RNA, poly I:C Poly I:C Polyinosinic:polycytidylic acid is an immunostimulant. It is used in the form of its sodium salt to simulate viral infections.... |
virus Virus A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea... es |
TRIF Trif TIR-domain-containing adapter-inducing interferon-β is an adapter in responding to activation of toll-like receptors . It mediates the rather delayed cascade of two TLR-associated signaling cascades, where the other one is dependent upon a MyD88 adapter.Toll-like receptors recognize specific... |
cell compartment |
|
| TLR 4 TLR 4 Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR 4 is a toll-like receptor. It detects lipopolysaccharide from Gram-negative bacteria and is thus important in the activation of the innate immune system... |
lipopolysaccharide Lipopolysaccharide Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major... |
Gram-negative bacteria | MyD88/MAL/TRIF/TRAM | cell surface |
|
| several heat shock protein Heat shock protein Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated... s |
Bacteria and host cells | ||||
| fibrinogen Fibrinogen Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for... |
host cells | ||||
| heparan sulfate Heparan sulfate Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins... fragments |
host cells | ||||
| hyaluronic acid fragments | host cells | ||||
| nickel Nickel Nickel is a chemical element with the chemical symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel belongs to the transition metals and is hard and ductile... |
|||||
| Numerous others | |||||
| TLR 5 TLR 5 Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene.- Function :The protein encoded by this gene is a member of the Toll-like receptor family which plays a fundamental role in pathogen recognition and activation of innate immunity... |
flagellin Flagellin Flagellin is a protein that arranges itself in a hollow cylinder to form the filament in bacterial flagellum. It has a mass of about 30,000 to 60,000 daltons... |
Bacteria | MyD88 | cell surface |
|
| TLR 6 | multiple diacyl lipopeptides | Mycoplasma Mycoplasma Mycoplasma refers to a genus of bacteria that lack a cell wall. Without a cell wall, they are unaffected by many common antibiotics such as penicillin or other beta-lactam antibiotics that target cell wall synthesis. They can be parasitic or saprotrophic. Several species are pathogenic in humans,... |
MyD88/MAL | cell surface |
|
| TLR 7 TLR 7 Toll-like receptor 7, also known as TLR7, is protein that in humans is encoded by the TLR7 gene. Orthologs are found in mammals and birds.- Function :... |
imidazoquinoline Imidazoquinoline Imidazoquinoline is a double cyclic organic molecule; its derivatives and compounds are often used for antiviral and antiallergic creams.... |
small synthetic compounds | MyD88 | cell compartment |
|
| loxoribine (a guanosine Guanosine Guanosine is a purine nucleoside comprising guanine attached to a ribose ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate , cyclic guanosine monophosphate , guanosine diphosphate , and guanosine triphosphate... analogue) |
|||||
| bropirimine Bropirimine Bropirimine is an experimental drug with anti-cancer and anti-viral properties. It is an orally effective immunomodulator and is being tried in bladder cancers.-Chemistry:... |
|||||
| single-stranded RNA | |||||
| TLR 8 | small synthetic compounds; single-stranded RNA | MyD88 | cell compartment |
|
|
| TLR 9 TLR9 Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. TLR9 has also been designated as CD289 .- Function :... |
unmethylated CpG Oligodeoxynucleotide CpG Oligodeoxynucleotide CpG oligodeoxynucleotides are short single-stranded synthetic DNA molecules that contain a cytosine "C" followed by a guanine "G". The "p" refers to the phosphodiester backbone of DNA, however some ODN have a modified phosphorothioate backbone. When these CpG motifs are unmethlyated, they act as... DNA |
Bacteria | MyD88 | cell compartment |
|
| TLR 10 | unknown | unknown | ? | ||
| TLR 11 | Profilin Profilin Profilin is an actin-binding protein involved in the dynamic turnover and restructuring of the actin cytoskeleton. It is found in all eukaryotic organisms in most cells. Profilin is important for spatially and temporally controlled growth of actin microfilaments, which is an essential process in... |
Toxoplasma gondii | MyD88 | cell compartment |
|
| TLR 12 | unknown | unknown | ? |
|
|
| TLR 13 | unknown | Virus | MyD88, TAK-1 | cell compartment |
Activation and effects
Following activation by ligands of microbial origin, several reactions are possible. Immune cells can produce signalling factors called cytokineCytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s, which trigger inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. In the case of a bacterial factor, the pathogen might be phagocytosed and digested, and its antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s 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
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
). Immune cells that have detected a virus may also release anti-viral factors such as interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
s.
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. 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
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
. 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.
Drugs interactions
ImiquimodImiquimod
Imiquimod is a prescription medication that acts as an immune response modifier. It is marketed by Meda AB, Graceway Pharmaceuticals and iNova Pharmaceuticals under the trade names Aldara and Zyclara, and by Mochida as Beselna. It is also referred to as R-837.- History :The original FDA approval...
(cardinally used in dermatology
Dermatology
Dermatology is the branch of medicine dealing with the skin and its diseases, a unique specialty with both medical and surgical aspects. A dermatologist takes care of diseases, in the widest sense, and some cosmetic problems of the skin, scalp, hair, and nails....
), and its successor resiquimod
Resiquimod
Resiquimod is a drug that acts as an immune response modifier, and has antiviral and antitumour activity. It is used as a topical cream in the treatment of skin lesions such as those caused by herpes simplex virus, and as an adjuvant to increase the effectiveness of vaccines...
, are ligands for TLR7 and TLR8.
The lipid A
Lipid A
Lipid A is a lipid component of an endotoxin held responsible for toxicity of Gram-negative bacteria. It is the innermost of the three regions of the lipopolysaccharide molecule, and its hydrophobic nature allows it to anchor the LPS to the outer membrane...
analogon eritoran
Eritoran
Eritoran is an investigational drug for the treatment of severe sepsis, an excessive inflammatory response to an infection. It is being developed by Eisai Co. and administered intravenously as eritoran tetrasodium. , a Phase III clinical trial is recruiting patients.-Mechanism of action:Toll-like...
acts as a TLR4 antagonist. , it is being developed as a drug against severe sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
.