Biology:Toll-like receptor 8
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Toll-like receptor 8 is a protein that in humans is encoded by the TLR8 gene.[1] TLR8 has also been designated as CD288 (cluster of differentiation 288). It is a member of the toll-like receptor (TLR) family.
Function
TLR8 seems to function differently in humans and mice. Until recently, TLR8 was believed to be nonfunctional in mice, but it seems to counteract TLR7 activity[2][3]
The TLR family 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 gene is predominantly expressed in lung and peripheral blood leukocytes, and lies in close proximity to another family member, TLR7, on chromosome X.[4] Recent research has also shown the expression of TLR8 in hippocampal interneurons, with yet unknown function.[5]
TLR8 can recognize GU-rich single-stranded RNA.[6] However, the presence of GU-rich sequences in the single-stranded RNA is not sufficient to stimulate TLR8.[7] TLR8 recognizes G-rich oligonucleotides.[8] TLR8 is activated by ssRNA and forms a dimer complex when uridine released from the degraded ssRNA binds at one active site in between the dimers and a short oligonucleotide binds to another active site on the surface of the TLR8 structure.[9]
TLR8 is an endosomal receptor that recognizes single stranded RNA (ssRNA), and can recognize ssRNA viruses such as Influenza, Sendai, and Coxsackie B viruses. TLR8 binding to the viral RNA recruits the myeloid differentiation primary response protein 88 (MyD88) and leads to activation of the transcription factor NF-κB and an antiviral response that leads to proinflammatory cytokine synthesis.[10][11] TLR8 recognizes single-stranded RNA of viruses such as HIV and HCV.[6][7] TLR8 is also involved in the activation of dendritic cells to produce inflammatory factors to help regulate tumor growth, so TLR8 is often used as a target in the research for therapies in treating cancers including ovarian cancer and lymphomas.[11]
Clinical significance
Genetic variants in TLR8 has recently been linked to susceptibility to pulmonary tuberculosis.[12]
As a drug target
- TLR8 agonists (e.g. VTX-2337) have undergone clinical trials as immune stimulants in combination therapy for some cancers.[13]
- TLR8 antagonists (e.g. CU-CPT9a) may have therapeutic applications against autoimmune disorders.[14]
References
- ↑ "Three novel mammalian toll-like receptors: gene structure, expression, and evolution". European Cytokine Network 11 (3): 362–71. September 2000. PMID 11022119. http://www.jle.com/medline.md?issn=1148-5493&vol=11&iss=3&page=362.
- ↑ "TLR8 deficiency leads to autoimmunity in mice". The Journal of Clinical Investigation 120 (10): 3651–62. October 2010. doi:10.1172/JCI42081. PMID 20811154.
- ↑ "Human Toll-like receptor 8 can be cool too: implications for foreign RNA sensing". Journal of Interferon & Cytokine Research 32 (8): 350–61. August 2012. doi:10.1089/jir.2012.0014. PMID 22817608.
- ↑ "Entrez Gene: TLR8 toll-like receptor 8". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51311.
- ↑ Seizer L, Rahimi S, Santos-Sierra S, Drexel M (2022) Expression of toll like receptor 8 (TLR8) in specific groups of mouse hippocampal interneurons. PLoS ONE 17(5): e0267860. https://doi.org/10.1371/journal.pone.0267860
- ↑ 6.0 6.1 "Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8". Science 303 (5663): 1526–9. March 2004. doi:10.1126/science.1093620. PMID 14976262. Bibcode: 2004Sci...303.1526H.
- ↑ 7.0 7.1 "HCV RNA Activates APCs via TLR7/TLR8 While Virus Selectively Stimulates Macrophages Without Inducing Antiviral Responses". Scientific Reports 6: 29447. July 2016. doi:10.1038/srep29447. PMID 27385120. Bibcode: 2016NatSR...629447Z.
- ↑ "Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function". Science 309 (5739): 1380–4. August 2005. doi:10.1126/science.1113401. PMID 16123302. Bibcode: 2005Sci...309.1380P.
- ↑ "Toll-like receptor 8 senses degradation products of single-stranded RNA". Nature Structural & Molecular Biology 22 (2): 109–115. February 2015. doi:10.1038/nsmb.2943. PMID 25599397.
- ↑ "TLR7 and TLR8: Key players in the antiviral response - Innate immunity". invivoGen. Fall 2006. http://www.invivogen.com/review-tlr7-tlr8.
- ↑ 11.0 11.1 "Recent trends in the development of Toll-like receptor 7/8-targeting therapeutics". Expert Opinion on Drug Discovery 16 (8): 869–880. August 2021. doi:10.1080/17460441.2021.1898369. PMID 33678093.
- ↑ "Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis". PLOS Genetics 4 (10): e1000218. October 2008. doi:10.1371/journal.pgen.1000218. PMID 18927625.
- ↑ "Immune Stimulant No Help When Added to Chemotherapy for Recurrent Ovarian Cancer.". Targeted Oncology. March 2017. http://www.targetedonc.com/conference/sgo-2017/immune-stimulant-no-help-when-added-to-chemotherapy-for-recurrent-ovarian-cancer.
- ↑ "Small-Molecule TLR8 Antagonists via Structure-Based Rational Design". Cell Chemical Biology 25 (10): 1286–1291.e3. October 2018. doi:10.1016/j.chembiol.2018.07.004. PMID 30100350.
Further reading
- "Toll-like receptors". Critical Care Medicine 30 (1 Suppl): S1-11. January 2002. doi:10.1097/00003246-200201001-00001. PMID 11782555.
- "Toll-like receptors as adjuvant receptors". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1589 (1): 1–13. February 2002. doi:10.1016/S0167-4889(01)00182-3. PMID 11909637.
External links
- Toll-Like+Receptor+8 at the US National Library of Medicine Medical Subject Headings (MeSH)
- PDBe-KB provides an overview of all the structure information available in the PDB for Human Toll-like receptor 8 (TLR8)
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