Where is tlr4 expressed

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Don't show this again. Search Fields » Search result. Gene name. Class Biological process Molecular function Disease. External id. Reliability Enhanced Supported Approved Uncertain. Reliability Supported Approved. Validation Supported Approved Uncertain. Annotation Intracellular and membrane Secreted - unknown location Secreted in brain Secreted in female reproductive system Secreted in male reproductive system Secreted in other tissues Secreted to blood Secreted to digestive system Secreted to extracellular matrix.

Searches Enhanced Supported Approved Uncertain Intensity variation Spatial variation Cell cycle intensity correlation Cell cycle spatial correlation Cell cycle biologically Custom data cell cycle dependant Cell cycle dependent protein Cell cycle independent protein Cell cycle dependent transcript Cell cycle independent transcript Multilocalizing Localizing 1 Localizing 2 Localizing 3 Localizing 4 Localizing 5 Localizing 6 Main location Additional location.

Type Protein Rna. Phase G1 S G2 M. Cell type. Expression Not detected Low Medium High. Cell type Any Alveolar cells type 1 Alveolar cells type 2 B-cells Basal glandular cells Basal keratinocytes Bipolar cells Cardiomyocytes Cholangiocytes Ciliated cells Club cells Collecting duct cells Cone photoreceptor cells Cytotrophoblasts Distal tubular cells Ductal cells Early spermatids Endothelial cells Enterocytes Erythroid cells Exocrine glandular cells Extravillous trophoblasts Fibroblasts Glandular cells Granulocytes Hepatocytes Hofbauer cells Horizontal cells Intestinal endocrine cells Ito cells Kupffer cells Late spermatids Leydig cells Macrophages Melanocytes Monocytes Mucus-secreting cells Muller glia cells Pancreatic endocrine cells Paneth cells Peritubular cells Proximal tubular cells Rod photoreceptor cells Sertoli cells Smooth muscle cells Spermatocytes Spermatogonia Suprabasal keratinocytes Syncytiotrophoblasts T-cells Undifferentiated cells Urothelial cells.

Category Cell type enriched Group enriched Cell type enhanced Low cell type specificity Not detected Detected in all Detected in many Detected in some Detected in single Is highest expressed. Category Cell line enriched Group enriched Cell line enhanced Low cell line specificity Not detected Detected in all Detected in many Detected in some Detected in single Is highest expressed.

Category Lineage enriched Group enriched Lineage enhanced Low lineage specificity Not detected Detected in all Detected in many Detected in single Is highest expressed. Prognosis Favorable Unfavorable. Antibodies Yes No. Tissue proteome. General description of the gene and the encoded protein s using information from HGNC and Ensembl , as well as predictions made by the Human Protein Atlas project.

Official gene symbol, which is typically a short form of the gene name, according to HGNC. Full gene name according to HGNC. Assigned HPA protein class es for the encoded protein s.

Read more. All transcripts of all genes have been analyzed regarding the location s of corresponding protein based on prediction methods for signal peptides and transmembrane regions. Genes with at least one transcript predicted to encode a secreted protein, according to prediction methods or to UniProt location data , have been further annotated and classified with the aim to determine if the corresponding protein s are secreted or actually retained in intracellular locations or membrane-attached.

Remaining genes, with no transcript predicted to encode a secreted protein, will be assigned the prediction-based location s. Number of protein-coding transcripts from the gene as defined by Ensembl. Summary of data presented in the Tissue Atlas and representative images of protein expression left and mRNA expression right. The images are clickable and will redirect to more Tissue Atlas data. Mutations in the TLR4 gene can inhibit the immune responses against the pathogens specifically recognized by the ancestor receptor.

Human TLR4 gene is composed of three exons. Their alignment to the TLR4 protein is illustrated in Figure 3. Figure 3. Alignment of human TLR4 gene and protein. Exon 1 encodes a signal peptide and initial amino acids of the extracellular domain. Exon 2 encodes first LRRs in the extracellular domain. Exon 3 encodes the remaining extracellular domain hypervariable region and LRRs , the transmembrane domain and the cytoplasmic domain.

TM, transmembrane domain; HYP, hypervariable region. As indicated in Table 1 , TLR4 genes are highly conserved across mammalian species.

Among different TLR4 sub-regions, the intracellular TIR-domain is highly conserved across species suggesting that the signal transduction pathways of TLR4 are also similar across species.

By contrast, TLR4 extracellular domains exhibit considerable sequence divergence and the LRRs are highly polymorphic 10 , 42 , For example, Lizundia et al. Table 1. Pair-wise alignment of the extracellular domain of human TLR4 with those of other species indicates that the most divergent region of TLR4 is its ligand recognition domain, in which different species exhibit a wide variety of surface electric charge 42 — The first amino acids of the proximal region of the TLR4 extracellular domain are poorly conserved across species and are highly variable for individuals in the same species.

The human TLR4 consists of an extracellular domain of amino acids residues 1— , a transmembrane domain of 33 amino acids residues — , a proximal cytoplasmic domain of amino acids residues — , and a distal cytoplasmic domain of 19 amino acids residues — The ectodomain consists of 21 LRRs amino acids 55— of the extracellular domain The human TLR4 also displays many single nucleotide polymorphisms SNPs particularly in the ectodomain of the protein, although most of these have only mildly deleterious phenotypic effects Table 2.

Comparison of the organization of human, porcine, and murine TLR4 genes. However, some differences exist even among NHPs. For instance, humans and chimpanzees are generally considered to be very sensitive to LPS, whereas baboons are highly resistant 46 , The baboon and human TLR4 amino acid sequences share The baboon TLR4 transmembrane domain sequence differs from the human sequence in one out of 30 residues, and in the proximal cytoplasmic domain by only 1 out of amino acids.

The carboxyl terminal domain is less similar to its human counterpart, with 16 of the last 21 human residues not replicated in the baboon protein, resulting in a protein that is 13 amino acids shorter than the human protein Table 3.

The authors suggested that this variation in the distal cytoplasmic region of TLR4 might be a reason for interspecies differences in LPS sensitivity. However, since TIR is instead located in the proximal cytoplasmic region, whether such mutations were functionally essential was in question Table 3.

Indeed, most mutations in these TIR-domains would likely have been deleterious. The TIR-domains of the rhesus macaque display a high level of similarity with their respective human counterparts with only two differences out of amino acids. The mouse gene produces a longer pre-mRNA sequence than its human counterpart, i. Each murine exon corresponds to a homologous sequence in the human gene. Mouse MD-2 also displays some discrete structural differences relative to the human counterpart in terms of electric charge properties Human MD-2 is more cationic than mouse MD This disparity includes residues close to the LPS binding site that are positively charged in the human MD These differences impact not only the secretion but also the function of MD-2, thus the activation of TLR4.

Across mouse strains, the TLR4 locus exhibits some genetic variations too. Among 35 strains of Mus musculus , 10 different alleles are identified on the basis of mutations at 22 sites, compared to a common reference sequence Some strains have accumulated more mutations than others.

This substitution is expected to alter the topology of the TLR4 signaling domain and potentially disrupt protein—protein interactions with down-stream molecules. These observations support the hypothesis that their mutant phenotype is due to a loss of TLR4 function. Four hundred fifteen genes are identified by cDNA microarray analysis as LPS-inducible and temporally regulated in bone marrow-derived macrophages of the four LPS-responsive strains. Thus, this set of genes represents possible down-stream targets specific to TLR4 signaling pathways.

Most of the genes induced encode components of the cytoskeleton or the phagosome, which correlates with the morphological changes that occur in bone marrow-derived macrophages upon LPS stimulation.

Thirty elements corresponding to 22 genes involved in cell growth, cycling, and differentiation belong to the TLR4-dependent transcriptional pathway. Because the amino acid similarity shared with the human amino acid hypervariable region is greater in the rabbit than in the mouse, the rabbit TLR4 may recognize human pathogens better than the mouse TLR4 This, and the greater overall similarity between rabbit and human TLR4, suggests that the human immune response to some pathogens may be better modeled in rabbits than in mice.

As in humans and mice, the porcine TLR4 gene is made up of three exons. The open reading frame ORF of bp encodes amino acid protein Overall, the predicted porcine TLR4 protein contains a amino acid putative leader peptide, an extracellular domain of residues 24— , a hydrophobic transmembrane region of 21 residues — , a proximal cytoplasmic region — , and a cytoplasmic TIR-domain of residues — The extracellular domain includes 21 LRRs of 20 to 29 residues 42 , Again, most of the amino acid differences among these species are located in a region between residues and , which corresponds to the amino acid hypervariable region involved in ligand recognition However, the canine gene lacks the two first exons found in other TLR4 genes 42 , Sequence alignment confirms that this is not due to a loss of introns or a different exon sequence organization Accession numbers: Genbank O and Genbank BAB Despite extensive sequence similarity among mammalian TLR4s, species-specific variations in their extracellular domains cause these receptors to have different spectrums of agonists and antagonists.

In addition, there is substantial diversity in the TLR4 cellular expression pattern and tissue distribution. Consequently, TLR4 functions vary across different species Table 4 summarizes the TLR4 expression patterns in the following species: humans, NHP, mice, rats, swine, rabbits, and dogs.

The predominant TLR4 expressing cells in humans are of myeloid origin. This TLR4 expression level decreases markedly during immature DC formation but remain clearly detectable Moderate levels of TLR4 expression are detected in the colon, ovary, lungs, small intestine, and placenta, whereas TLR4 expression is low in the brain, heart, kidneys, liver, prostate, pancreas, testis, muscle, and thymus.

No TLR4 expression was detected in skeletal muscle or skin 53 , 56 , Further investigations using for example immunohistochemistry, could help to determine whether TLR4 is expressed by tissue cells or by cells of blood origin, in particular for organs like liver and lungs. TLR4 is constitutively expressed in the human fat tissue with a clear detection in adipocytes, and its expression is not regulated following LPS treatment In the human central nervous system CNS , TLR4 is expressed by two types of non-neuronal supportive cells: the CNS residential macrophages or microglia and the macroglial cells such as astrocytes Astrocytes and oligodendrocytes also slightly express TLR4.

In astrocytes, TLR4 is exclusively localized on the cell surface and is not detectable within intracellular vesicles. This difference in the TLR4 subcellular localization may be linked to the different phagocytic and antigen processing properties of microglia and astrocytes.

Development of multiple sclerosis lesions in humans is associated with higher levels of TLR4 expression. TLR4 may be involved in cardiovascular diseases. For example, elevated levels of TLR4 have been found in the tissues of failed hearts and ischemic hearts Expression of TLR4 has been also detected in intestinal epithelial cell lines 69 , Although normal human ileal epithelium barely expresses TLR4, its expression is up-regulated in inflammatory bowel disease IBD.

Although the currently available evidence is limiting, no fundamental differences between humans and NHPs at the level or pattern of TLR4 expression have been reported. Consequently, these pDCs do not undergo any differentiation or morphological changes in response to stimulation with E. Intestinal epithelial cells normally restrict the entry of LPS in the circulation.

However, inflammatory or non-inflammatory e. Given that TLR4 is expressed in the apical membrane of ileal epithelial cells, the presence of LPS in the ileal lumen may stimulate epithelial cells through TLR4 and induce the production of chemoattractant factors for neutrophils and inflammatory cytokines. LPS that has been translocated from the villous epithelium can then be taken up by neutrophils, which then migrate to the portal circulation via the epithelium and lamina propria.

Nevertheless, species-specific similarities and differences have been noted among different NHP species. For example, human and baboon arterial endothelial cells display a low but similar basal expression of TLR4 This could explain why baboon arterial endothelial cells appeared being resistant to the pro-inflammatory effects of LPS and the lack of vascular response to LPS in baboons. In mice, as in humans, cells of myeloid origin such as monocytes, macrophages, microglia, myeloid DCs, and granulocytes exhibit the highest levels of TLR4 expression.

This leads to lipid accumulation in macrophages. This process leads to actin polymerization, a step required for membrane ruffling that likely promotes antigen uptake. However, Syk-independent pathways may also contribute to the TLR4-dependent antigen uptake. Altogether, these murine data suggest an important pro-inflammatory role for mmLDL in macrophage activation through a TLR4-dependent pathway.

Murine TLR4 mRNA is abundant in the lungs, heart, and spleen and, as in humans, is sparse in the muscle, liver, and kidneys 10 , 17 , 53 , although further investigation is needed to clarify the cell types that express it in these tissues. Neither the mouse astrocytes nor oligodendrocytes do In CNS cell cultures, LPS induces significant injury to developing oligodendrocytes, only in the presence of microglia As oligodendrocytes lack TLR4, these findings suggest that the activation of TLR4 signaling by LPS in microglia leads to indirect injury to oligodendrocyte precursors, which are susceptible to reactive oxygen species and pro-inflammatory cytokines.

Similar to humans, TLR4 is also involved in cardiovascular diseases in mice 67 , Murine TLR4 is up-regulated after myocardial infarction and is involved in myocardial dysfunction during bacterial sepsis. TLR4 regulates maladaptive left ventricular remodeling that occur post-infarction, probably via inflammatory cytokine production and matrix degradation. When infected with T. A bp insertion between the second and third exon is produced by an alternative splicing.

This novel exon contains an in-frame stop codon at bp. The alternatively spliced variant contains a part of the extracellular domain of TLR4 that interacts with LPS 56 , In addition to the secreted smTLR4, a significant amount of smTLR4 is entrapped in the cell membrane, where it may mediate antagonistic effects as well through interacting with newly synthesized TLR4 or CD14 and thus blocking TLR4 signal transduction. Nonetheless, a human counterpart of the smTLR4 remains to be confirmed.

Lipopolysaccharide increases TLR4 expression in human macrophages and monocytes. In contrast, TLR4 expression decreases in mouse peritoneal macrophages and neutrophils after LPS challenge and remains unaffected in mouse monocytes 55 , Schroder et al. Although TLR4 target genes are more rapidly induced in human macrophages than in mouse macrophages following LPS exposure, several negative feedback regulators of the TLR4 pathway are more rapidly induced and to a greater degree in mouse macrophages.

This enhanced negative feedback regulation may further reduce the primary LPS response in mouse macrophages, thereby contributing to the lower endotoxin sensitivity in mice compared to humans. Another difference between mouse and human TLR4 probably lies in the LPS recognition spectrum of the receptor complex. For example, human TLR4, but not murine TLR4, can discriminate between the hexa- and penta-acylated forms of LPS produced by Pseudomonas aeruginosa from the airways of cystic fibrosis patients.

Dunant 3, Varese, Italy. They are highly conserved receptors that recognize conserved pathogen-associated molecular patterns PAMPs , thus representing the first line of defense against infections.

In addition, it also binds endogenous molecules produced as a result of tissue injury. Hence, TLR4 represents a key receptor on which both infectious and noninfectious stimuli converge to induce a proinflammatory response.

TLR4-mediated inflammation, triggered by exogenous or endogenous ligands, is also involved in several acute and chronic diseases, having a pivotal role as amplifier of the inflammatory response.

This review focuses on the research progress about the role of TLR4 activation in infectious and noninfectious e. The first function described for TLR4 was the recognition of exogenous molecules from pathogens pathogen-associated molecular pattern molecules PAMPs , in particular the molecules from gram-negative bacteria e. Recently, it has been widely demonstrated that TLR4 is also involved in the recognition of endogenous molecules released by injured tissues and necrotic cells.

These molecules, called damage-associated molecular pattern molecules DAMPs , induce the activation of a strong proinflammatory response through interaction with TLR4 [ 2 ]. Generally, inflammation has a protective role. It is a complex and coordinated process followed by the induction of resolution pathways that restore tissue integrity and function. TLR4 is expressed on the cell surface on both hematopoietic and nonhematopoietic cells, including endothelial cells [ 3 ], cardiac myocytes [ 4 ], and cells of the central nervous system CNS [ 5 ].

TLR4 is composed of a residue extracellular domain and a residue intracellular domain that is involved in the intracellular signaling cascade [ 6 ]. It has been demonstrated that transfection of TLR4 alone is not enough for LPS recognition, and physical association of TLR4 with myeloid differentiation 2 MD2 on the cell surface is required for ligand-induced activation [ 7 — 9 ].

Detailed crystallographic data are reported elsewhere [ 11 — 13 ]. MyDmediated signaling occurs mainly at the plasma membrane and involves a rapid recruitment of MyD88 and MAL proteins. CD14 favors receptor complex internalization [ 14 ], even though also CDindependent translocation of the receptor complex to the endosome and TRIF signaling has been recently demonstrated [ 16 ].

Beyond the induction at the transcriptional level of proinflammatory mediators, TLR4 interaction with LPS also orchestrates the induction of mediators such as microRNAs miRNAs that posttranscriptionally regulate the shutdown of the proinflammatory response and induce a state of temporary refractoriness to further LPS stimulation.

Therefore, a tight regulation of TLR4 signaling is important in tissue homeostasis to avoid excessive inflammation and to induce tissue repair following infection or injury [ 17 , 18 ]. Exogenous ligands PAMPs are molecules isolated from bacteria, viruses, fungi, plants, and cyanobacteria.

However, from bacteria and cyanobacteria Rhodobacter and Oscillatoria species, resp. These antagonists were employed both in vitro and in vivo in animal models of diseases, allowing investigation of the effects of TLR4 signaling modulation [ 29 , 30 ].

Endogenous ligands DAMPs belong to two main groups: a molecules originated from extracellular matrix and [ 31 — 35 ] b intracellular mediators passively released or actively secreted by cells [ 36 — 49 ]. A prototypic molecule of the extracellular matrix that can induce TLR4-mediated inflammation is the glycosaminoglycan hyaluronan.

After tissue injury, it is degraded into small fragments, which have been shown to activate macrophages via TLR4 both in vitro and in vivo [ 31 , 51 ].

After cell damage and necrosis, these molecules are released in the extracellular milieu, thus inducing a strong proinflammatory response mediated by TLR4 [ 36 , 40 , 52 ]. Beyond its role in sterile inflammation, HMGB1 is also actively released by immunocompetent cells after exposure to the products of pathogenic bacteria, thus representing a common mediator at the intersection of infectious and noninfectious inflammatory response [ 36 ].

Some studies have linked TLR4 polymorphisms to an increased susceptibility to sepsis due to gram-negative infection; other studies failed to confirm this reviewed in [ 58 ]. Indeed, the recruitment and activation of neutrophils produce the release of reactive oxygen and nitrogen species and of proteolytic enzymes that are highly cytotoxic and exacerbate tissue damage [ 66 ].

The results demonstrated that TLR4 signaling on both donor and recipient cells contributes to systemic and intragraft inflammatory response [ 76 ]. The results suggest that the downregulation of TLR4-induced proinflammatory response has beneficial effects in reducing tissue damage [ 77 , 78 ] and this was associated, in the experiments with the cyanobacterial antagonist, with a reduced number of polymorphonuclear leukocytes infiltrating the ischemic area [ 78 ].

Our preliminary data unpublished results in a mouse model of acute myocardial infarction using the cyanobacterial TLR4 antagonist suggest that early inhibition of TLR4 signaling just before reperfusion positively affects tissue remodeling, since long-term cardiac function was better in mice treated with the antagonist in comparison to mice treated with vehicle. However, further in-depth studies are needed to clarify the role of TLR4 signaling in tissue repair.

Neuroinflammation is the common hallmark of several neurodegenerative and neurological diseases [ 80 — 82 ]. In the CNS, microglial cells are resident phagocytes that constantly control the extracellular environment and sense for the presence of pathogens or injured cells.

Microglial activation by noxious stimuli represents a defensive response with the aim to restore tissue homeostasis. It has been reported that direct TLR4 stimulation with LPS produces immediate and long-term memory deficits in mice models of endotoxemia, especially in aged mice [ 84 , 85 ].

In this contest, the role of TLR4 is not clear, probably due to the complex mechanisms controlling reacting microglia phenotypes [ 80 , 93 ].

In support of this hypothesis, Michaud et al. In this context, MPLA was shown to induce a potent phagocytic response by microglia while triggering a moderate inflammatory response in vivo. The studies about the role of TLR4 in other neurodegenerative and neurological diseases, ALS and epilepsy, gave more clear results.

In a mouse genetic model of ALS superoxide dismutase 1-mutant mice , chronic administration of LPS once every 2 weeks for 3 months in presymptomatic mice accelerated motor neuron degeneration and disease progression [ ]. Furthermore, De Paola et al. In epilepsy, analyses of hippocampal specimens obtained at surgery from patients with drug-resistant temporal lobe epilepsy showed increased TLR4 and HMGB1 expression in glial cells astrocytes and neurons [ ].

Intriguingly, antagonists targeting TLR4 were shown to delay seizure onset and decrease acute and chronic seizure recurrence [ ]. Since its discovery, a great deal of experimental data supported TLR4 as a key player of the inflammatory process due to both infectious and noninfectious stimuli.

In several pathological conditions TLR4 engagement contributes to disease resolution; however, when TLR4 activation pathways are poorly regulated, it can contribute to disease progression. The authors declare that there are no competing interests regarding the publication of this paper. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Special Issues. Academic Editor: Marisa I. Received 16 Mar Accepted 04 May Published 18 May Introduction The first function described for TLR4 was the recognition of exogenous molecules from pathogens pathogen-associated molecular pattern molecules PAMPs , in particular the molecules from gram-negative bacteria e.

TLR4 Signaling TLR4 is expressed on the cell surface on both hematopoietic and nonhematopoietic cells, including endothelial cells [ 3 ], cardiac myocytes [ 4 ], and cells of the central nervous system CNS [ 5 ].

Figure 1. TLR4 intracellular signaling pathways. TLR signaling is triggered by ligand-induced dimerization of the receptors. MyDdependent pathway induces production of proinflammatory cytokines, and MyDindependent pathway induces the production of type I interferons.

Table 1. References S. Akira and K. View at: Google Scholar L. Yu, L. Wang, and S. Taylor, J. Trowbridge, J. Rudisill, C. Termeer, J. Simon, and R. Frantz, L. Kobzik, Y. Kim et al. Medzhitov, P.

Preston-Hurlburt, and C. Janeway Jr. Nagai, S. Akashi, M. Nagafuku et al. Schromm, E. Lien, P. Henneke et al. Shimazu, S. Akashi, H. Ogata et al. Viriyakosol, P. Tobias, R. You can create and edit multiple shopping carts. Edit mode — allows you to edit or modify an existing requisition prior to submitting. You will be able to modify only the cart that you have PunchedOut to, and won't have access to any other carts.

Inspect mode — when you PunchOut to Bio-Rad from a previously created requisition but without initiating an Edit session, you will be in this mode. You cannot modify any Cart contents. Click here to find out how. Toll-like receptors TLRs are one of the key receptor families forming an initial line of defence against invading pathogens. Like other PRRs, they are germline encoded, functioning to recognize and eliminate microbial non-self antigens.