Toll-like receptor

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Toll-like receptor
TLR3 structure.png
The curved leucine-rich repeat region of toll-like receptors, represented here by TLR3
SymbolToll-like receptor
Membranome 7

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached 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. Humans lack genes for TLR11, TLR12 and TLR13 [1] and mice lack a functional gene for TLR10. [2] 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]


The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of immune receptors called toll-like receptors (TLRs) that are expressed on the membranes of leukocytes including dendritic cells, macrophages, natural killer cells, cells of the adaptive immunity T cells, and B cells, and non-immune cells (epithelial and endothelial cells, and fibroblasts). [5]

The binding of ligands - either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection - to the TLR marks the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity. [6] [7]

Upon activation, TLRs recruit adaptor proteins (proteins that mediate other protein-protein interactions) within the cytosol of the immune cell to propagate the antigen-induced signal transduction pathway. These recruited proteins are then responsible for the subsequent activation of other downstream proteins, including protein kinases (IKKi, IRAK1, IRAK4, and TBK1) that further amplify the signal and ultimately lead to the upregulation or suppression of genes that orchestrate inflammatory responses and other transcriptional events. Some of these events lead to cytokine production, proliferation, and survival, while others lead to greater adaptive immunity. [7] If the ligand is 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.

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]


TIR domain from TLR2. This is a signal transduction domain distinct from the LRR domain discussed earlier. TLR2.png
TIR domain from TLR2. This is a signal transduction domain distinct from the LRR domain discussed earlier.

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). In addition to the recognition of exogenous PAMPs, TLRs can also bind to endogenous damage-associated molecular patterns (DAMPs) such as heat shock proteins (HSPs) or plasma membrane constituents. [9] 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.

Extended family

TLRs are present in vertebrates as well as 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. [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. [11] [12] [13] 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 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 Toll Pathway of Drosophila melanogaster.jpg
The Toll immunity pathway as found in the fruit fly

The involvement of toll signalling in immunity was first demonstrated in the fruit fly, Drosophila melanogaster . [19] Fruit flies have only innate immune responses allowing studies to avoid interference of adaptive immune mechanisms on signal transduction. The fly response to fungal or bacterial infection occurs through two distinct signalling cascades, one of which is the toll pathway and the other is the immune deficiency pathway. The toll pathway is similar to mammalian TLR signalling, but unlike mammalian TLRs, toll is not activated directly by pathogen-associated molecular patterns (PAMPs). Its receptor ectodomain recognizes the cleaved form of the cytokine spätzle, which is secreted in the 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 Gram positive bacteria, fungi and virulence factors. [17] [20] First, the Spätzle processing enzyme (SPE) is activated in response to infection and cleaves spätzle (spz). Cleaved spätzle then binds to the toll receptor and crosslinks its ectodomains. This triggers conformational changes in the receptor resulting in signalling through toll. From this point forward, the signalling cascade is very similar to mammalian signalling through TLRs. The toll-induced signalling complex (TICS) is composed of 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 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 has also been designated as CD282 (cluster of differentiation 282).


TLR3 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. [23]


As noted above, human cells do not express TLR11, but mice cells do. Mouse-specific TLR11 recognizes uropathogenic 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 Salmonella Typhi, which causes food- and waterborne gastroenteritis and typhoid fever in humans. TLR11 deficient knockout mice, on the other hand, are efficiently infected. As a result, this knockout mouse can act as a 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 compartments. Furthermore, they are expressed by different types of leucocytes or other cell types:

ReceptorLigand(s) [26] Ligand location [26] Adapter(s)LocationCell types [26]
TLR 1 multiple triacyl lipopeptides Bacterial lipoprotein MyD88/MALcell surface
TLR 2 multiple glycolipids Bacterial peptidoglycansMyD88/MALcell surface
multiple lipopeptides and proteolipids Bacterial peptidoglycans
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/TRAMcell surface
several heat shock proteins Bacteria and host cells
fibrinogen host cells
heparan sulfate fragmentshost cells
hyaluronic acid fragmentshost cells
nickel [31]
Various opioid drugs
TLR 5 Bacterial flagellin BacteriaMyD88cell 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/MALcell surface
  • monocytes/macrophages
  • Mast cells
  • B lymphocytes
TLR 7 imidazoquinoline small synthetic compoundsMyD88cell compartment
loxoribine (a guanosine analogue)
single-stranded RNARNA viruses
TLR 8 small synthetic compounds; single-stranded Viral RNA, phagocytized bacterial RNA(24)MyD88cell 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 DNABacteria, DNA virusesMyD88cell compartment
  • monocytes/macrophages
  • Plasmacytoid dendritic cells [28]
  • B lymphocytes
TLR 10 triacylated lipopeptides [34] unknowncell surface
TLR 11 Profilin Toxoplasma gondii [38] MyD88cell compartment [39]
Flagellin Bacteria (E. coli, Salmonella) [24]
TLR 12 Profilin Toxoplasma gondii [40] MyD88cell 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, bacteriaMyD88, TAK-1cell compartment
  • monocytes/macrophages
  • conventional dendritic cells


Toll-Like Receptor (TLR) ligands among RNA and DNA viruses, Gram-positive and Gram-negative bacteria, fungi, and protists Toll-Like Receptors (TLRs).png
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 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. 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 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. [49]


Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations. Toll-like receptor pathways.svg
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 fight 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 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 (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 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 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 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. [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]

TLR4 has been shown to be important for the long-term side-effects of opioids. Its activation leads to downstream release of inflammatory modulators including TNF-α and IL-1β, and constant low-level release of these modulators is thought to reduce the efficacy of opioid drug treatment with time, and is involved in opioid tolerance, [57] [58] hyperalgesia and allodynia. [59] [60] Morphine induced TLR4 activation attenuates pain suppression by opioids and enhances the development of opioid tolerance and addiction, drug abuse, and other negative side effects such as 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]


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.

The prototypic member of the family, the toll receptor ( P08953 ; Tl) in the fruit fly Drosophila melanogaster , was discovered in 1985 by 1995 Nobel Laureates Christiane Nüsslein-Volhard and Eric Wieschaus and colleagues. It was known for its developmental function in embryogenesis by establishing the dorsal-ventral axis. It was named after Christiane Nüsslein-Volhard's 1985 exclamation, "Das ist ja toll!" ("That's amazing!"), in reference to the underdeveloped ventral portion of a fruit fly larva. [4] It was cloned by the laboratory of Kathryn Anderson in 1988. [68] 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, 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, [69] mapped to a chromosome by Taguchi and colleagues in 1996. [70] 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. [71]

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. [7] TLR 4 function as an LPS sensing receptor was discovered by Bruce A. Beutler and colleagues. [72] 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.

The history of Toll-like receptors History of TLRs.jpg
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

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Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

<span class="mw-page-title-main">Toll-like receptor 3</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 3 (TLR3) also known as CD283 is a protein that in humans is encoded by the TLR3 gene. TLR3 is a member of the toll-like receptor family of pattern recognition receptors of the innate immune system. TLR3 recognizes double-stranded RNA in endosomes, which is a common feature of viral genomes internalised by macrophages and dendritic cells.

<span class="mw-page-title-main">IRAK4</span> Protein-coding gene in humans

IRAK-4, in the IRAK family, is a protein kinase involved in signaling innate immune responses from Toll-like receptors. It also supports signaling from T-cell receptors. IRAK4 contains domain structures which are similar to those of IRAK1, IRAK2, IRAKM and Pelle. IRAK4 is unique compared to IRAK1, IRAK2 and IRAKM in that it functions upstream of the other IRAKs, but is more similar to Pelle in this trait. IRAK4 has important clinical applications.

<span class="mw-page-title-main">MYD88</span> Protein-coding gene in the species Homo sapiens

Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the MYD88 gene.

<span class="mw-page-title-main">Toll-like receptor 2</span> One of the toll-like receptors and plays a role in the immune system

Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the TLR2 gene. TLR2 has also been designated as CD282. TLR2 is one of the toll-like receptors and plays a role in the immune system. TLR2 is a membrane protein, a receptor, which is expressed on the surface of certain cells and recognizes foreign substances and passes on appropriate signals to the cells of the immune system.

<span class="mw-page-title-main">Toll-like receptor 1</span> One of the toll-like receptors and plays a role in the immune system

Toll-like receptor 1 (TLR1) is a member of Toll-like receptors (TLRs), which is a family of pattern recognition receptors (PRRs) that form the cornerstone of the innate immune system. TLR1 recognizes bacterial lipoproteins and glycolipids in complex with TLR2. TLR1 is a cell surface receptor. TLR1 is in humans encoded by the TLR1 gene, which is located on chromosome 4.

<span class="mw-page-title-main">TICAM1</span> Protein-coding gene in the species Homo sapiens

TIR domain containing adaptor molecule 1 is an adapter in responding to activation of toll-like receptors (TLRs). It mediates the rather delayed cascade of two TLR-associated signaling cascades, where the other one is dependent upon a MyD88 adapter.

<span class="mw-page-title-main">Toll-like receptor 5</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene. It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria. It has been shown to be involved in the onset of many diseases, which includes Inflammatory bowel disease. Recent studies have also shown that malfunctioning of TLR5 is likely related to rheumatoid arthritis, osteoclastogenesis, and bone loss. Abnormal TLR5 functioning is related to the onset of gastric, cervical, endometrial and ovarian cancers.

<span class="mw-page-title-main">Toll-like receptor 4</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an intracellular signaling pathway NF-κB and inflammatory cytokine production which is responsible for activating the innate immune system.

<span class="mw-page-title-main">Toll-like receptor 6</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 6 is a protein that in humans is encoded by the TLR6 gene. TLR6 is a transmembrane protein, member of toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. TLR6 acts in a heterodimer form with toll-like receptor 2 (TLR2). Its ligands include multiple diacyl lipopeptides derived from gram-positive bacteria and mycoplasma and several fungal cell wall saccharides. After dimerizing with TLR2, the NF-κB intracellular signalling pathway is activated, leading to a pro-inflammatory cytokine production and activation of innate immune response. TLR6 has also been designated as CD286.

<span class="mw-page-title-main">Toll-like receptor 9</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. TLR9 has also been designated as CD289. It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expressed in immune system cells including dendritic cells, macrophages, natural killer cells, and other antigen presenting cells. TLR9 is expressed on endosomes internalized from the plasma membrane, binds DNA, and triggers signaling cascades that lead to a pro-inflammatory cytokine response. Cancer, infection, and tissue damage can all modulate TLR9 expression and activation. TLR9 is also an important factor in autoimmune diseases, and there is active research into synthetic TLR9 agonists and antagonists that help regulate autoimmune inflammation.

<span class="mw-page-title-main">Toll-like receptor 10</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 10 is a protein that in humans is encoded by the TLR10 gene. TLR10 has also been designated as CD290 . TLR10 has not been extensively studied because it is a pseudogene in mice, though all other mammalian species contain an intact copy of the TLR10 gene. Unlike other TLRs, TLR10 does not activate the immune system and has instead been shown to suppress inflammatory signaling on primary human cells. This makes TLR10 unique among the TLR family. TLR10 was thought to be an "orphan" receptor, however, recent studies have identified ligands for TLR10 and these include HIV-gp41. Ligands for TLR2 are potential ligands for TLR10.

<span class="mw-page-title-main">IRAK1</span> Protein-coding gene in the species Homo sapiens

Interleukin-1 receptor-associated kinase 1 (IRAK-1) is an enzyme in humans encoded by the IRAK1 gene. IRAK-1 plays an important role in the regulation of the expression of inflammatory genes by immune cells, such as monocytes and macrophages, which in turn help the immune system in eliminating bacteria, viruses, and other pathogens. IRAK-1 is part of the IRAK family consisting of IRAK-1, IRAK-2, IRAK-3, and IRAK-4, and is activated by inflammatory molecules released by signaling pathways during pathogenic attack. IRAK-1 is classified as a kinase enzyme, which regulates pathways in both innate and adaptive immune systems.

<span class="mw-page-title-main">Bruce Beutler</span> American immunologist and geneticist

Bruce Alan Beutler is an American immunologist and geneticist. Together with Jules A. Hoffmann, he received one-half of the 2011 Nobel Prize in Physiology or Medicine, for "discoveries concerning the activation of innate immunity." Beutler discovered the long-elusive receptor for lipopolysaccharide. He did so by identifying spontaneous mutations in the gene coding for mouse Toll-like receptor 4 (Tlr4) in two unrelated strains of LPS-refractory mice and proving they were responsible for that phenotype. Subsequently, and chiefly through the work of Shizuo Akira, other TLRs were shown to detect signature molecules of most infectious microbes, in each case triggering an innate immune response.

<span class="mw-page-title-main">SIGIRR</span> Protein-coding gene in the species Homo sapiens

Single Ig IL-1-related receptor (SIGIRR), also called Toll/Interleukin-1 receptor 8 (TIR8) or Interleukin-1 receptor 8 (IL-1R8), is transmembrane protein encoded by gene SIGIRR, which modulate inflammation, immune response, and tumorigenesis of colonic epithelial cells.

<span class="mw-page-title-main">Toll-interleukin receptor</span>

The toll-interleukin-1 receptor (TIR) homology domain is an intracellular signaling domain found in MyD88, SARM1, interleukin-1 receptors, toll receptors and many plant R proteins. It contains three highly conserved regions, and mediates protein-protein interactions between the toll-like receptors (TLRs) and signal-transduction components. TIR-like motifs are also found in plant proteins where they are involved in resistance to disease and in bacteria where they are associated with virulence. When activated, TIR domains recruit cytoplasmic adaptor proteins MyD88 (UniProt Q99836) and TOLLIP (toll-interacting protein, UniProt Q9H0E2). In turn, these associate with various kinases to set off signaling cascades. Some TIR domains have also been found to have intrinsic NAD+ cleavage activity, such as in SARM1. In the case of SARM1, the TIR NADase activity leads to the production of Nam, ADPR and cADPR and the activation of downstream pathways involved in Wallerian degeneration and neuron death.

Murine caspase-11, and its human homologs caspase-4 and caspase-5, are mammalian intracellular receptor proteases activated by TLR4 and TLR3 signaling during the innate immune response. Caspase-11, also termed the non-canonical inflammasome, is activated by TLR3/TLR4-TRIF signaling and directly binds cytosolic lipopolysaccharide (LPS), a major structural element of Gram-negative bacterial cell walls. Activation of caspase-11 by LPS is known to cause the activation of other caspase proteins, leading to septic shock, pyroptosis, and often organismal death.

The interleukin-1 receptor (IL-1R) associated kinase (IRAK) family plays a crucial role in the protective response to pathogens introduced into the human body by inducing acute inflammation followed by additional adaptive immune responses. IRAKs are essential components of the Interleukin-1 receptor signaling pathway and some Toll-like receptor signaling pathways. Toll-like receptors (TLRs) detect microorganisms by recognizing specific pathogen-associated molecular patterns (PAMPs) and IL-1R family members respond the interleukin-1 (IL-1) family cytokines. These receptors initiate an intracellular signaling cascade through adaptor proteins, primarily, MyD88. This is followed by the activation of IRAKs. TLRs and IL-1R members have a highly conserved amino acid sequence in their cytoplasmic domain called the Toll/Interleukin-1 (TIR) domain. The elicitation of different TLRs/IL-1Rs results in similar signaling cascades due to their homologous TIR motif leading to the activation of mitogen-activated protein kinases (MAPKs) and the IκB kinase (IKK) complex, which initiates a nuclear factor-κB (NF-κB) and AP-1-dependent transcriptional response of pro-inflammatory genes. Understanding the key players and their roles in the TLR/IL-1R pathway is important because the presence of mutations causing the abnormal regulation of Toll/IL-1R signaling leading to a variety of acute inflammatory and autoimmune diseases.

An innate immune defect is a defect in the innate immune response that blunts the response to infection. These defects may occur in monocytes, neutrophils, natural killer cells, basophils, mast cells or complement proteins.

Jonathan C. Kagan is an American immunologist and the Marian R. Neutra, Ph.D. Professor of Pediatrics at Harvard Medical School. He is also the director of Basic Research and Shwachman Chair in Gastroenterology at Boston Children's Hospital. Kagan is a world leader in defining the molecular basis of innate immunity and inflammation.