TLR4

TLR4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4G8A, 2Z62, 2Z63, 2Z65, 2Z66, 3FXI, 3UL7, 3UL8, 3UL9, 3ULA
Identifiers
Aliases	TLR4, ARMD10, CD284, TLR-4, TOLL, toll like receptor 4
External IDs	OMIM: 603030 MGI: 96824 HomoloGene: 41317 GeneCards: TLR4
Gene ontology Molecular function • lipopolysaccharide receptor activity • lipopolysaccharide binding • protein binding • transmembrane signaling receptor activity • receptor activity Cellular component • cytoplasm • membrane • perinuclear region of cytoplasm • cell surface • integral component of membrane • plasma membrane • endosome membrane • intrinsic component of plasma membrane • integral component of plasma membrane • lipopolysaccharide receptor complex • external side of plasma membrane Biological process • positive regulation of MHC class II biosynthetic process • positive regulation of JNK cascade • TRIF-dependent toll-like receptor signaling pathway • positive regulation of interleukin-12 biosynthetic process • cellular response to mechanical stimulus • positive regulation of interleukin-8 production • positive regulation of ERK1 and ERK2 cascade • T-helper 1 type immune response • interferon-gamma production • positive regulation of platelet activation • positive regulation of interleukin-1 production • positive regulation of stress-activated MAPK cascade • positive regulation of NLRP3 inflammasome complex assembly • positive regulation of interleukin-12 production • positive regulation of interferon-alpha production • regulation of cytokine secretion • positive regulation of interferon-beta biosynthetic process • I-kappaB phosphorylation • positive regulation of nitric-oxide synthase biosynthetic process • interleukin-1 beta secretion • positive regulation of B cell proliferation • defense response to bacterium • positive regulation of interleukin-6 production • activation of innate immune response • positive regulation of tumor necrosis factor production • positive regulation of interleukin-8 biosynthetic process • negative regulation of tumor necrosis factor production • innate immune response • negative regulation of interleukin-17 production • I-kappaB kinase/NF-kappaB signaling • positive regulation of interferon-beta production • positive regulation of inflammatory response • toll-like receptor 4 signaling pathway • positive regulation of macrophage cytokine production • positive regulation of tumor necrosis factor biosynthetic process • positive regulation of interleukin-10 production • immune system process • astrocyte development • intestinal epithelial structure maintenance • positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway • response to lipopolysaccharide • activation of MAPK activity • cellular response to lipoteichoic acid • positive regulation of NF-kappaB transcription factor activity • immune response • negative regulation of interleukin-23 production • regulation of inflammatory response • positive regulation of chemokine production • lipopolysaccharide-mediated signaling pathway • detection of fungus • positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway • negative regulation of interferon-gamma production • response to bacterium • negative regulation of osteoclast differentiation • B cell proliferation involved in immune response • positive regulation of nitric oxide biosynthetic process • negative regulation of interleukin-6 production • positive regulation of interferon-gamma production • nitric oxide production involved in inflammatory response • MyD88-dependent toll-like receptor signaling pathway • regulation of dendritic cell cytokine production • positive regulation of gene expression • negative regulation of ERK1 and ERK2 cascade • positive regulation of I-kappaB kinase/NF-kappaB signaling • macrophage activation • positive regulation of NF-kappaB import into nucleus • detection of lipopolysaccharide • cellular response to lipopolysaccharide • positive regulation of lymphocyte proliferation • positive regulation of transcription from RNA polymerase II promoter • MyD88-independent toll-like receptor signaling pathway • signal transduction • inflammatory response • defense response to Gram-negative bacterium • toll-like receptor signaling pathway • necroptotic process • apoptotic signaling pathway • negative regulation of MyD88-independent toll-like receptor signaling pathway Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7099	21898
Ensembl	ENSG00000136869	ENSMUSG00000039005
UniProt	O00206	Q9QUK6
RefSeq (mRNA)	NM_138557 NM_003266 NM_138554 NM_138556	NM_021297
RefSeq (protein)	NP_003257.1 NP_612564.1 NP_612567.1	NP_067272.1
Location (UCSC)	Chr 9: 117.7 – 117.72 Mb	Chr 4: 66.83 – 66.93 Mb
PubMed search	[1]	[2]
Wikidata

View/Edit Human

View/Edit Mouse

Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene.^[3][4] TLR 4 is a toll-like receptor which is responsible for activating the innate immune system. It is most well known for recognizing lipopolysaccharide (LPS), a component present in many Gram-negative bacteria (e.g. Neisseria spp) and select Gram-positive bacteria. Its ligands also include several viral proteins, polysaccharide, and a variety of endogenous proteins such as low-density lipoprotein, beta-defensins, and heat shock protein.^[5]

TLR 4 has also been designated as CD284 (cluster of differentiation 284). The molecular weight of TLR 4 is approximately 95 kDa.

Function

The protein encoded by this gene is a member of the Toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity.

The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta, and in myelomonocytic subpopulation of the leukocytes.

It cooperates with LY96 (also referred as MD-2) and CD14 to mediate in signal transduction events induced by lipopolysaccharide (LPS)^[6] found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness.

Several transcript variants of this gene have been found, but the protein-coding potential of most of them is uncertain.^[7]

Evolutionary history

TLR4 originated when TLR2 and TLR4 diverged about 500 million years ago near the beginning of vertebrate evolution.^[8] Sequence alignments of human and great ape TLR4 exons have demonstrated that not much evolution has occurred in human TLR4 since our divergence from our last common ancestor with chimpanzees; human and chimp TLR4 exons only differ by three substitutions while humans and baboons are 93.5% similar in the extracellular domain.^[9] Notably, humans possess a greater number of early stop codons in TLR4 than great apes; in a study of 158 humans worldwide, 0.6% had a nonsense mutation.^[10][11] This suggests that there are weaker evolutionary pressures on the human TLR4 than on our primate relatives. The distribution of human TLR4 polymorphisms matches the out-of-Africa migration, and it is likely that the polymorphisms were generated in Africa before migration to other continents.^[11][12]

Interactions

TLR 4 has been shown to interact with:

• Lymphocyte antigen 96,^[13][14]
• Myd88,^{[15][16][17][18]} and
• TOLLIP.^[19]

Intracellular trafficking of TLR4 is dependent on the GTPase Rab-11a, and knock down of Rab-11a results in hampered TLR4 recruitment to E. coli-containing phagosomes and subsequent reduced signal transduction through the MyD88-independent pathway.^[20]

Clinical significance

Various single nucleotide polymorphisms (SNPs) of the TLR4 in humans have been identified^[21] and for some of them an association with increased susceptibility to Gram-negative bacterial infections ^[22] or faster progression and a more severe course of sepsis in critically ill patients was reported.^[23]

In pregnancy

Activation of TLR4 in intrauterine infections leads to deregulation of prostaglandin synthesis, leading to uterine smooth muscle contraction.

Asp299Gly polymorphism

Classically, TLR4 is said to be the receptor for LPS, however TLR 4 has also been shown to be activated by other kinds of lipids. Plasmodium falciparum, a parasite known to cause the most common and serious form of malaria that is seen primarily in Africa, produces glycosylphosphatidylinositol, which can activate TLR4.^[24] Two SNPs in TLR4 are co-expressed with high penetrance in African populations (i.e. TLR-4-Asp299Gly and TLR-4-Thr399Ile). These Polymorphisms are associated with an increase in TLR4-Mediated IL-10 production—an immunomodulator—and a decrease in proinflammatory cytokines.^[25] The TLR-4-Asp299Gly point mutation is strongly correlated with an increased infection rate with Plasmodium falciparum. It appears that the mutation prevents TLR4 from acting as vigorously against, at least some plasmodial infections. The malaria infection rate and associated morbidity are higher in TLR-4-Asp299Gly group, but mortality appears to be decreased. This may indicate that at least part of the pathogenesis of malaria takes advantage of cytokine production. By reducing the cytokine production via the TLR4 mutation, the infection rate may increase, but the number of deaths due to the infection seem to decrease.^[24]

In addition, TLR4-D299G has been associated with aggressive colorectal cancer in humans. It has been shown that human colon adenocarcinomas from patients with TLR4-D299G were more frequently of an advanced stage with metastasis than those with wild-type TLR4. The same study demonstrated functionally that intestinal epithelial cells (Caco-2) expressing TLR4-D299G underwent epithelial-mesenchymal transition and morphologic changes associated with tumor progression, whereas intestinal epithelial cells expressing wild-type TLR4 did not.^[26]

Animal studies

A link between the TLR 4 receptor and binge drinking has been suggested. When genes responsible for the expression of TLR 4 and GABA receptors are manipulated in rodents that had been bred and trained to drink excessively, the animals showed a "profound reduction" in drinking behaviours.^[27] Additionally, it has been shown that ethanol, even in the absence of LPS, can activate TLR4 signaling pathways.^[28]

High levels of TLR4 molecules and M2 tumor-associated macrophages are associated with increased susceptibility to cancer growth in mice deprived of sleep. Mice genetically modified so that they could not produce TLR4 molecules showed normal cancer growth.^[29]

Drugs targeting TLR4

Toll-like receptor 4 has been shown to be important for the long-term side-effects of opioid analgesic drugs. Various μ-opioid receptor ligands have been tested and found to also possess action as agonists or antagonists of TLR4, with opioid agonists such as morphine being TLR4 agonists, while opioid antagonists such as naloxone were found to be TLR4 antagonists. Activation of TLR4 leads to downstream release of inflammatory modulators including TNF-α and Interleukin-1, and constant low-level release of these modulators is thought to reduce the efficacy of opioid drug treatment with time, and be involved in both the development of tolerance to opioid analgesic drugs,^[30][31] and in the emergence of side-effects such as hyperalgesia and allodynia that can become a problem following extended use of opioid drugs.^[32][33] 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,^[34][35] and this has also been demonstrated with drugs that block TLR4 itself. Interestingly the response of TLR4 to opioid drugs has been found to be enantiomer-independent, so the "unnatural" enantiomers of opioid drugs such as morphine and naloxone, which lack affinity for opioid receptors, still produce the same activity at TLR4 as their "normal" enantiomers.^[36][37] This means that the unnatural enantiomers of opioid antagonists, such as (+)-naloxone, can be used to block the TLR4 activity of opioid analgesic drugs, while leaving the μ-opioid receptor mediated analgesic activity unaffected.^[38])^[37][39] This may also be the mechanism behind the beneficial effect of ultra-low dose naltrexone on opioid analgesia.^[40]

Morphine causes inflammation by binding to the protein lymphocyte antigen 96, which, in turn, causes the protein to bind to Toll-like receptor 4 (TLR4).^[41] The 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. Drug candidates that target TLR4 may improve opioid-based pain management therapies.^[42]

Agonists

• Buprenorphine^[43]
• Carbamazepine^[44]
• Ethanol^[45]
• Fentanyl^[43]
• Levorphanol^[43]
• Lipopolysaccharides (LPS)^[46]
• Methadone^[43]
• Morphine^[43]
• Oxcarbazepine^[44]
• Oxycodone^[43]
• Pethidine^[43]

• Glucuronoxylomannan from Cryptococcus^[47][48]
• Morphine-3-glucuronide (inactive at opioid receptors, so selective for TLR4 activation)^[33][43]
• Tapentadol (mixed agonist/antagonist)
• "Unnatural" isomers such as (+)-morphine activate TLR4 but lack opioid receptor activity,^[36] although (+)-morphine also shows activity as a sigma receptor agonist.^[49]

Antagonists

• The lipid A analog eritoran acts as a TLR4 antagonist. As of December 2009, it was being developed as a drug against severe sepsis.^[50] However, in 2013, a news story said the results against sepsis were somewhat disappointing and that it was better used to treat certain cases of severe influenza. Although it does not treat the virus itself, it could be used against the massive immune reaction called cytokine storm which often occurs later in the infection and is a major cause of mortality from severe influenza.^[51]

• Amitriptyline^[44]
• Cyclobenzaprine^[44]
• Ketotifen^[44]
• Imipramine^[44]
• Mianserin^[44]
• Ibudilast^[52]
• Naloxone^[43]
• Naltrexone^[43]
• (+)-naltrexone^[43]
• LPS-RS^[43]
• Propentofylline
• Tapentadol (mixed agonist/antagonist)

• (+)-naloxone ("unnatural" isomer, lacks opioid receptor affinity so selective for TLR4 inhibition)^[37]

References

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2. "Mouse PubMed Reference:".
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Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations

Further reading

• Lien E, Ingalls RR (2002). "Toll-like receptors". Crit. Care Med. 30 (1 Suppl): S1–11. doi:10.1097/00003246-200201001-00001. PMID 11782555.
• Raetz CR, Whitfield C (2002). "Lipopolysaccharide Endotoxins". Annu. Rev. Biochem. 71: 635–700. doi:10.1146/annurev.biochem.71.110601.135414. PMC 2569852. PMID 12045108.
• Lin WJ, Yeh WC (2005). "Implication of Toll-like receptor and tumor necrosis factor alpha signaling in septic shock". Shock. 24 (3): 206–9. doi:10.1097/01.shk.0000180074.69143.77. PMID 16135957.
• Lorenz E (2007). "TLR2 and TLR4 expression during bacterial infections". Curr. Pharm. Des. 12 (32): 4185–93. doi:10.2174/138161206778743547. PMID 17100621.
• Stoll LL, Denning GM, Weintraub NL (2007). "Endotoxin, TLR4 signaling and vascular inflammation: potential therapeutic targets in cardiovascular disease". Curr. Pharm. Des. 12 (32): 4229–45. doi:10.2174/138161206778743501. PMID 17100625.
• Rousseaux C, Desreumaux P (2007). "[The peroxisome-proliferator-activated gamma receptor and chronic inflammatory bowel disease (PPARgamma and IBD)]". J. Soc. Biol. 200 (2): 121–31. doi:10.1051/jbio:2006015. PMID 17151549.
• Wang PF, Fang H, Chen J, Lin S, Liu Y, Xiong XY, Wang YC, Xiong RP, Lv FL, Wang J, Yang QW (2014). "Polyinosinic-polycytidylic acid has therapeutic effects against cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via TLR3". J Immunol. 192 (10): 4783–94. doi:10.4049/jimmunol.1303108. PMC 4009499. PMID 24729619.
• Szabo G, Dolganiuc A, Dai Q, Pruett SB (2007). "TLR4, ethanol, and lipid rafts: a new mechanism of ethanol action with implications for other receptor-mediated effects". J. Immunol. 178 (3): 1243–9. doi:10.4049/jimmunol.178.3.1243. PMID 17237368.

External links

• Toll-Like Receptor 4 at the US National Library of Medicine Medical Subject Headings (MeSH)