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Toll-like receptor
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'''Toll-like receptors''' (TLRs) are a class of proteins that play a key role in the [[innate immune system]]. Ten toll-like receptors have been identified in humans; TLR1 to TLR10.<ref name="Nie2018">{{Cite journal | title = Toll-Like Receptors, Associated Biological Roles, and Signaling Networks in Non-Mammals | date = 2018 | url=https://www.frontiersin.org/article/10.3389/fimmu.2018.01523|journal=Frontiers in Immunology|volume=9 | last =Nie | first = Li | last2 = Cai | first2 = Shi-Yu | last3 = Shao | first3 = Jian-Zhong | last4 = Chen | first4 = Jiong|doi=10.3389/fimmu.2018.01523|pmc=PMC6043800|pmid=30034391|issn=1664-3224}}</ref> They are type I transmembrane [[glycoprotein]]s, and are expressed on several immune cell types including [[dendritic cell]]s, [[macrophage]]s, [[B cell]]s, and [[natural killer cell]]s.<ref name="Kemball2010">{{Cite journal | last = Kemball | first = Christopher C | last2 = Alirezaei | first2 = Mehrdad | last3 = Whitton | first3 = J Lindsay | date = Sep 2010 | title = Type B coxsackieviruses and their interactions with the innate and adaptive immune systems|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3045535/|journal=Future microbiology|volume=5|issue=9|pages=1329–1347|doi=10.2217/fmb.10.101|issn=1746-0913|pmc=3045535|pmid=20860480|quote=|via=}}</ref> ==Types of Toll-like receptors== Ten types of toll-like receptors have been identified in humans. {| class="wikitable" ! colspan="11" |Types of Toll-like receptors |- |Type |Anatomy |Cell types |Location |Triggers |Knock out mice (genetically engineered to be missing this receptor completely) |Human mutations |Agonists (increases activity) |Antagonists (decreases activity) |Diseases associated with increased activity |Diseases associated with decreased activity |- |[[Toll-like receptor 1|TLR1]] |[[small intestine|small]] and [[large intestine|large]] intestine |[[macrophage]]s, [[neutrophil]]s |cytoplasmic membrane |[[gram-positive]] bacteria, [[Borrelia burgdorferi]]<ref name="PMC2546821">{{Cite journal | last =Bernardino | first = Andrea L. F. | last2 = Myers | first2=Tereance A. | last3 = Alvarez | first3 = Xavier | last4 = Hasegawa | first4 = Atsuhiko| last5 = Philipp | first5 = Mario T. | date = Oct 2008 | title = Toll-Like Receptors: Insights into Their Possible Role in the Pathogenesis of Lyme Neuroborreliosis|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2546821/|journal=Infection and Immunity|volume=76|issue=10|pages=4385–4395|doi=10.1128/IAI.00394-08|issn=0019-9567|pmc=2546821|pmid=18694963|quote=|via=}}</ref><ref name="PMC4898433">{{Cite journal | last =Rahman | first = Shusmita | last2 = Shering | first2 = Maria | last3 = Ogden | first3=Nicholas H | last4 = Lindsay | first4 = Robbin| last5 = Badawi | first5 = Alaa | date = 2016-05-31 | title = Toll-like receptor cascade and gene polymorphism in host–pathogen interaction in Lyme disease|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898433/|journal=Journal of Inflammation Research|volume=9|issue= | pages = 91–102|doi=10.2147/JIR.S104790|issn=1178-7031|pmc=4898433|pmid=27330321|quote=|via=}}</ref><ref name="J1469" /><ref name="J0025998">{{Cite journal | last= Joosten | first = Leo A. B. | last2 = Netea | first2 = Mihai G. | last3 = Meer | first3 = Jos W. M. van der | last4 = Kullberg | first4 = Bart-Jan| last5 = Adema | first5 = Gosse J. | last6 = Sturm | first6 = Patrick | last7 = Hofstede | first7 = Hadewych ter | last8 = Oosting | first8 = Marije | date = 2011-10-05 | title = TLR1/TLR2 Heterodimers Play an Important Role in the Recognition of Borrelia Spirochetes|url=https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0025998|journal=PLOS ONE|language=en|volume=6|issue=10| pages = e25998|doi=10.1371/journal.pone.0025998|issn=1932-6203|pmc=3187844|pmid=21998742}}</ref> | |deficiency associated with heightened [[Th1]] inflammatory responses and antibiotic-refractory [[Lyme]] arthritis<ref>{{Cite journal | last =Strle | first = Klemen | last2 = Shin | first2=Junghee J. | last3 = Glickstein | first3 = Lisa J. | last4 = Steere | first4 = Allen C. | date = May 2012 | title = Association of a Toll-like receptor 1 polymorphism with heightened Th1 inflammatory responses and antibiotic-refractory Lyme arthritis|url=https://www.ncbi.nlm.nih.gov/pubmed/22246581|journal=Arthritis and Rheumatism|volume=64|issue=5|pages=1497–1507|doi=10.1002/art.34383|issn=1529-0131|pmc=3338893|pmid=22246581}}</ref> | | | | |- |[[Toll-like receptor 2|TLR2]] |[[lung]]s, [[kidney]]s, [[skin]], [[gastrointestinal tract]] |[[microglia]], [[Schwann cell]]s, [[monocyte]]s, [[macrophage]]s, [[dendritic cell]]s, [[polymorphonuclear leukocyte]]s, [[B cell]]s, [[T cell]]s |cytoplasmic membrane |[[Herpes simplex virus]]<ref name="PMC3465860" />, [[varicella zoster virus]]<ref name="PMC20510263">{{Cite journal | last =Gershon | first=Anne A. | last2 = Gershon | first2 = Michael D. | last3 = Breuer | first3 = Judith | last4 = Levin | first4 = Myron J. | last5 = Oaklander | first5 = Anne Louise | last6 = Griffiths | first6 = Paul D. | date = May 2010 | title = Advances in the understanding of the pathogenesis and epidemiology of herpes zoster |url =https://www.ncbi.nlm.nih.gov/pubmed/20510263/|journal=Journal of Clinical Virology: The Official Publication of the Pan American Society for Clinical Virology|volume=48 | issue = Suppl 1|pages=S2–7|doi=10.1016/S1386-6532(10)70002-0|issn=1873-5967|pmc=5391040|pmid=20510263|quote=|via=}}</ref>, [[heat shock protein]]s, [[cytomegalovirus]]<ref name="PMC12663765">{{Cite journal | last =Compton | first=Teresa | last2 = Kurt-Jones | first2=Evelyn A. | last3 = Boehme | first3 = Karl W. | last4 = Belko | first4 = John| last5 = Latz | first5 = Eicke | last6 = Golenbock | first6 = Douglas T. | last7 = Finberg | first7 = Robert W. | date = Apr 2003 | title = Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2|url=https://www.ncbi.nlm.nih.gov/pubmed/12663765/|journal=Journal of Virology|volume=77|issue=8|pages=4588–4596|issn=0022-538X|pmid=12663765}}</ref>,[[Epstein-Barr virus]]<ref name="PMC17522215">{{Cite journal | last =Gaudreault | first=Eric | last2 = Fiola | first2 = Stéphanie | last3 = Olivier | first3=Martin | last4 = Gosselin | first4 = Jean | date = Aug 2007 | title = Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2|url=https://www.ncbi.nlm.nih.gov/pubmed/17522215/|journal=Journal of Virology|volume=81|issue=15 | pages = 8016–8024|doi=10.1128/JVI.00403-07|issn=0022-538X|pmc=1951286|pmid=17522215}}</ref>, [[Borrelia burgdorferi]]<ref name="PMC2546821" /><ref name="PMC4898433" /><ref name="J1469">{{Cite journal | last =Singh | first = S.K. | last2 = Girschick | first2 = H.J. | date = Aug 2006 | title = Toll-like receptors in Borrelia burgdorferi-induced inflammation|url=https://linkinghub.elsevier.com/retrieve/pii/S1198743X14642567|journal=Clinical Microbiology and Infection|language=en|volume=12|issue=8 | pages = 705–717|doi=10.1111/j.1469-0691.2006.01440.x}}</ref><ref name="J0025998" /> |Reduced susceptibility to inflammatory damage following [[Herpes simplex virus#HSV-1|HSV-1]] infection<ref name="PMC3465860">{{Cite journal | last =West | first=John A. | last2 = Gregory | first2 = Sean M. | last3 = Damania | first3=Blossom | date = 2012-10-08 | title = Toll-like receptor sensing of human herpesvirus infection|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465860/|journal=Frontiers in Cellular and Infection Microbiology|volume=2|doi=10.3389/fcimb.2012.00122|issn=2235-2988|pmc=3465860|pmid=23061052}}</ref> | | |[[Nanocurcumin]]<ref name="fase830">{{Cite journal | last =Chen | first=Xinpu | last2 = Chenna | first2=Venugopal | last3 = Maitra | first3=Anirban | last4 = Devaraj | first4 = Sridevi | date = 2014-04-01 | title = Nanocurcumin attenuates inflammation by decreasing Toll-like receptor 2 and 4 expression and activity and promoting an anti-inflammatory macrophage phenotype (830.22)|url=https://www.fasebj.org/doi/abs/10.1096/fasebj.28.1_supplement.830.22|journal=The FASEB Journal|volume=28|issue=1_supplement | pages = 830.22|doi=10.1096/fasebj.28.1_supplement.830.22|issn=0892-6638}}</ref> | | |- |[[Toll-like receptor 3|TLR3]] |[[placenta]], [[pancreas]] |[[dentrite|dendritic]] [[leukocyte]]s |intracellular vesicles |[[dsRNA]] molecules |Increased susceptibility to [[Coxsackie B3]] infection<ref>{{Cite journal | last =Negishi | first = Hideo | last2 = Osawa | first2=Tomoko | last3 = Ogami | first3 = Kentaro | last4 = Ouyang | first4 = Xinshou | last5 = Sakaguchi | first5 = Shinya | last6 = Koshiba | first6 = Ryuji | last7 = Yanai | first7 = Hideyuki | last8 = Seko | first8 = Yoshinori | last9 = Shitara | first9 = Hiroshi | date = 2008-12-23 | title = A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity|url=https://www.ncbi.nlm.nih.gov/pubmed/19074283/|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=105|issue=51|pages=20446–20451|doi=10.1073/pnas.0810372105|issn=1091-6490|pmc=2629334|pmid=19074283}}</ref> |Deficiency associated with HSV-1 encephalitis<ref>{{Cite journal | last =Guo | first = Yiqi | last2 = Audry | first2 = Magali | last3 = Ciancanelli | first3 = Michael | last4 = Alsina | first4 = Laia| last5 = Azevedo | first5 = Joana | last6 = Herman | first6 = Melina | last7 = Anguiano | first7 = Esperanza | last8 = Sancho-Shimizu | first8 = Vanessa | last9 = Lorenzo | first9 = Lazaro | date = 2011-09-26 | title = Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity|url=https://www.ncbi.nlm.nih.gov/pubmed/21911422/|journal=The Journal of Experimental Medicine|volume=208|issue=10|pages=2083–2098|doi=10.1084/jem.20101568|issn=1540-9538|pmc=3182056|pmid=21911422}}</ref> |[[Ampligen]]<ref>http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM334430.pdf</ref> | | | |- |[[Toll-like receptor 4|TLR4]] |[[Monocyte]]s/[[macrophage]]s, [[dendritic cell]] subset, [[mast cell]]s, [[intestinal epithelium]]<ref name="ThaoBook" /> | |cytoplasmic membrane |[[lipopolysaccharide]]s,[[heat shock protein]],[[Coxsackie B3]]<ref name="P12707353" />, [[Coxsackie B4]] <ref name="P15452251" />, [[Herpes simplex virus#HSV-2|HSV-2]]<ref name="P19124006">{{Cite journal | last =Li | first = Hui | last2 = Li | first2 = Xiaoling | last3 = Wei | first3 = Yun | last4 = Tan | first4 = Yun| last5 = Liu | first5 = Xuefeng | last6 = Wu | first6 = Xinxing | date = 2009-02-13 | title = HSV-2 induces TLRs and NF-kappaB-dependent cytokines in cervical epithelial cells|url=https://www.ncbi.nlm.nih.gov/pubmed/19124006/|journal=Biochemical and Biophysical Research Communications|volume=379|issue=3 | pages = 686–690|doi=10.1016/j.bbrc.2008.12.150|issn=1090-2104|pmid=19124006}}</ref>, [[malaria]] |Reduced [[myocarditis]] and viral replication with [[Coxsackie B4]] infection.<ref name="P12707353" /> | |[[Ethanol]]<ref>{{Cite journal | last =Pascual | first = María | authorlink = | last2 = Baliño | first2 = Pablo|author-link2 = | last3 = Alfonso-Loeches | first3=Silvia | author-link3 = | last4 = Aragón | first4 = Carlos M.G. | authorlink4 = | last5 = Guerri | first5 = Consuelo | authorlink5 = | date = Jun 2011 | title = Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage|url=https://linkinghub.elsevier.com/retrieve/pii/S0889159111000626|journal=Brain, Behavior, and Immunity|language=en|volume=25|issue=|pages=S80–S91|doi=10.1016/j.bbi.2011.02.012|quote=|via=}}</ref>, adjuvants in some [[vaccine]]s<ref>{{Cite journal | last = Fox | first = Christopher B. | last2 = Friede | first2 = Martin | last3 = Reed | first3=Steven G. | last4 = Ireton | first4 = Gregory C. | date = 2010 | title=Synthetic and natural TLR4 agonists as safe and effective vaccine adjuvants|url=https://www.ncbi.nlm.nih.gov/pubmed/20593273|journal=Sub-Cellular Biochemistry|volume=53|pages=303–321|doi=10.1007/978-90-481-9078-2_14|issn=0306-0225|pmid=20593273}}</ref> |[[Amitriptyline]],[[Naltrexone]], Nanocurcumin<ref name="fase830" /> |[[ME/CFS]]<ref>http://www.medizin.uni-tuebingen.de/transfusionsmedizin/institut/eir/content/2014/94/article.pdf</ref> | |- |[[Toll-like receptor 5|TLR5]] | | |cytoplasmic membrane | | | | | | | |- |[[Toll-like receptor 6|TLR6]] | | |cytoplasmic membrane | | | | | | | |- |[[Toll-like receptor 7|TLR7]] |[[lung]], [[placenta]], and [[spleen]] | |intracellular vesicles |ssRNA and other small molecules, [[Epstein Barr virus]]<ref name="P17609264" /> | | |[[Imiquimod]] ||[[Plaquenil]] |[[Systemic lupus erythematosus]] (SLE) | |- |[[Toll-like receptor 8|TLR8]] | | |intracellular vesicles |[[ssRNA]] and other small molecules | | | | | | |- |[[Toll-like receptor 9|TLR9]] | | |intracellular vesicles | [[Herpes simplex virus#HSV-2|HSV-2]],<ref name="P19124006" /> [[varicella zoster virus]],<ref name="PMC20510263" /> [[Epstein Barr virus]]<ref name="P17609264">{{Cite journal | last =Martin | first=Heather J.|author-link = | last2 = Lee | first2 = Jae Myun|author-link2 = | last3 = Walls | first3=Dermot | author-link3 = | last4 = Hayward | first4 = S. Diane | authorlink4 = | date = Sep 2007 | title = Manipulation of the toll-like receptor 7 signaling pathway by Epstein-Barr virus|url=https://www.ncbi.nlm.nih.gov/pubmed/17609264/|journal=Journal of Virology|volume=81|issue=18 | pages = 9748–9758|doi=10.1128/JVI.01122-07|issn=0022-538X|pmc=2045431|pmid=17609264|quote=|via=}}</ref><ref name="P21191071">{{Cite journal | last =van Gent | first = Michiel | last2 = Griffin | first2=Bryan D. | last3 = Berkhoff | first3 = Eufemia G. | last4 = van Leeuwen | first4 = Daphne| last5 = Boer | first5 = Ingrid G.J. | last6 = Buisson | first6 = Marlyse | last7 = Hartgers | first7 = Franca C. | last8 = Burmeister | first8 = Wim P. | last9 = Wiertz | first9 = Emmanuel J. | date = 2011-02-01 | title = EBV lytic-phase protein BGLF5 contributes to TLR9 downregulation during productive infection|url=https://www.ncbi.nlm.nih.gov/pubmed/21191071/|journal=Journal of Immunology (Baltimore, Md.: 1950)|volume=186|issue=3|pages=1694–1702|doi=10.4049/jimmunol.0903120|issn=1550-6606|pmid=21191071}}</ref> | | | ||[[Plaquenil]] | | |- |[[Toll-like receptor 10|TLR10]] | | |intracellular vesicles | | | | | | | |- |} ==Infection== [[Coxsackie B4]] triggers TLR4 on human pancreatic cells<ref name="P15452251">{{Cite journal | last = Triantafilou | first = Kathy | last2 = Triantafilou | first2 = Martha | date = Oct 2004 | title = Coxsackievirus B4-induced cytokine production in pancreatic cells is mediated through toll-like receptor 4|url=https://www.ncbi.nlm.nih.gov/pubmed/15452251/|journal=Journal of Virology|volume=78|issue=20|pages=11313–11320|doi=10.1128/JVI.78.20.11313-11320.2004|issn=0022-538X|pmid=15452251|quote=|via=}}</ref>, TLR4 knock-out mice infected with [[Coxsackie B3]] showed reduced [[myocarditis]] and viral replication.<ref name="P12707353">{{Cite journal | last = Fairweather | first=DeLisa | last2 = Yusung | first2 = Susan | last3 = Frisancho | first3 = Sylvia | last4 = Barrett | first4 = Masheka| last5 = Gatewood | first5 = Shannon | last6 = Steele | first6 = Ronelle | last7 = Rose | first7 = Noel R. | date = 2003-05-01 | title = IL-12 receptor beta 1 and Toll-like receptor 4 increase IL-1 beta- and IL-18-associated myocarditis and coxsackievirus replication|url=https://www.ncbi.nlm.nih.gov/pubmed/12707353/|journal=Journal of Immunology (Baltimore, Md.: 1950)|volume=170|issue=9|pages=4731–4737|issn=0022-1767|pmid=12707353}}</ref> ==Genetics== TLR polymorphisms occur even within a species, and can significantly affect an individual’s susceptibility to infection and disease caused by a particular microbe.<ref>{{Cite journal | last =Berdeli | first = Afig | authorlink = | last2 = Celik | first2 = Handan Ak |author-link2 = | last3 = Ozyürek | first3 = Ruhi | author-link3 = | last4 = Dogrusoz | first4 = Buket | author-link4 = | last5 = Aydin | first5 = Hikmet Hakan | authorlink5 = | date = Jul 2005 | title = TLR-2 gene Arg753Gln polymorphism is strongly associated with acute rheumatic fever in children|url=https://www.ncbi.nlm.nih.gov/pubmed/15968536/|journal=Journal of Molecular Medicine (Berlin, Germany)|volume=83|issue=7|pages=535–541|doi=10.1007/s00109-005-0677-x|issn=0946-2716|pmid=15968536|quote=|via=}}</ref> ==Pharmacology== Drugs known to block TLRs include [[hydroxychloroquine]]. Several drugs that target TLRs are being studied for the treatment of cancer and inflammatory diseases.<ref>{{Cite journal | last =O'Neill | first = Luke A. J. | last2 = Parker | first2=Andrew E. | last3 = Hennessy | first3 = Elizabeth J. | date = Apr 2010 | title = Targeting Toll-like receptors: emerging therapeutics?|url=https://www.nature.com/articles/nrd3203|journal=Nature Reviews Drug Discovery|language=en|volume=9|issue=4|pages=293–307|doi=10.1038/nrd3203|issn=1474-1784|quote=|via=}}</ref> ==Learn more== *[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465860/ Toll-like receptor sensing of human herpesvirus infection] *[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3045535/ Type B coxsackieviruses and their interactions with the innate and adaptive immqune systems] *[https://books.google.co.uk/books?id=fEZrwuvrPKUC&lpg=PP1&dq=TLR2%20TRL10%20%20table&pg=PA17#v=onepage&q&f=false Toll-like Receptors (TLRs) table]<ref name="ThaoBook">{{Cite book | url=https://books.google.co.uk/books?id=fEZrwuvrPKUC&lpg=PP1&dq=TLR2%20TRL10%20%20table&pg=PA17#v=onepage&q&f=false | title = Immunology | last =Doan | first=Thao | last2 = Melvold | first2 = Roger | last3=Viselli | first3 = Susan | last4 = Valtenbaugh | first4 = Carl | date = 2012-08-28|publisher=Lippincott Williams & Wilkins|isbn=9781451109375|language=en}}</ref> ==See also== *[[Immune system]] *[[Innate immune system]] ==References== {{Reflist}} [[Category:Immunology]] [[Category:Proteins]] [[Category:Toll-like receptors]]
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