Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene.[1][2] 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. TLR 4 has also been designated as CD284 (cluster of differentiation 284). The molecular weight of TLR 4 is approximately 95 kDa.
Contents
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)[3] 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.[4]
Interactions
TLR 4 has been shown to interact with:
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.[12]
Clinical Significance
Various single nucleotide polymorphisms (SNPs) of the TLR4 in humans have been identified[13] and for some of them an association with increased susceptibility to Gram-negative bacterial infections [14] or faster progression and a more severe course of sepsis in critically ill patients was reported.[15]
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 parasitic infection seen primarily in Africa, produces glycosylphosphatidylinositol, which can activate TLR4.[16] 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.[17] 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.[16]
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.[18] Additionally, it has been shown that ethanol, even in the absence of LPS, can activate TLR4 signaling pathways.[19]
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.[20]
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,[21][22] and in the emergence of side-effects such as hyperalgesia and allodynia that can become a problem following extended use of opioid drugs.[23][24] 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,[25][26] 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.[27][28] 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.[29])[28][30] This may also be the mechanism behind the beneficial effect of ultra-low dose naltrexone on opioid analgesia.[31]
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).[32] The morphine-induced TLR4 activation attenuates pain suppression by opioid and enhances the development of opioid tolerance and addiction, drug abuse, and other negative side effects such as respiratory depression. Drug candidates that target TLR4 may improve opioid-based pain management therapies.[33]
Agonists
- Glucuronoxylomannan from Cryptococcus[38][39]
- Morphine-3-glucuronide (inactive at opioid receptors, so selective for TLR4 activation)[24][34]
- "Unnatural" isomers such as (+)-morphine activate TLR4 but lack opioid receptor activity,[27] although (+)-morphine also shows activity as a sigma receptor agonist.[40]
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.[41] 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, though it does not treat the virus itself but against the massive immune reaction called cytokine storm which occurs later in the infection and, sometimes in concert with sepsis (it can also help cause sepsis), sometimes alone, can kill.[42]
- (+)-naloxone ("unnatural" isomer, lacks opioid receptor affinity so selective for TLR4 inhibition)[28]
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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 et al. (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. 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)
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