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.[1] They are type I transmembrane glycoproteins, and are expressed on several immune cell types including dendritic cells, macrophages, B cells, and natural killer cells.[2]

Types of Toll-like receptors[edit | edit source]

Ten types of toll-like receptors have been identified in humans.

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
TLR1 small and large intestine macrophages, neutrophils cytoplasmic membrane gram-positive bacteria, Borrelia burgdorferi[3][4][5][6] deficiency associated with heightened Th1 inflammatory responses and antibiotic-refractory Lyme arthritis[7]
TLR2 lungs, kidneys, skin, gastrointestinal tract microglia, Schwann cells, monocytes, macrophages, dendritic cells, polymorphonuclear leukocytes, B cells, T cells cytoplasmic membrane Herpes simplex virus[8], varicella zoster virus[9], heat shock proteins, cytomegalovirus[10],Epstein-Barr virus[11], Borrelia burgdorferi[3][4][5][6] Reduced susceptibility to inflammatory damage following HSV-1 infection[8] Nanocurcumin[12]
TLR3 placenta, pancreas dendritic leukocytes intracellular vesicles dsRNA molecules Increased susceptibility to Coxsackie B3 infection[13] Deficiency associated with HSV-1 encephalitis[14] Ampligen[15]
TLR4 Monocytes/macrophages, dendritic cell subset, mast cells, intestinal epithelium[16] cytoplasmic membrane lipopolysaccharides,heat shock protein,Coxsackie B3[17], Coxsackie B4 [18], HSV-2[19], malaria Reduced myocarditis and viral replication with Coxsackie B4 infection.[17] Ethanol[20], adjuvants in some vaccines[21] Amitriptyline,Naltrexone, Nanocurcumin[12] ME/CFS[22]
TLR5 cytoplasmic membrane
TLR6 cytoplasmic membrane
TLR7 lung, placenta, and spleen intracellular vesicles ssRNA and other small molecules, Epstein Barr virus[23] Imiquimod Plaquenil Systemic lupus erythematosus (SLE)
TLR8 intracellular vesicles ssRNA and other small molecules
TLR9 intracellular vesicles HSV-2,[19] varicella zoster virus,[9] Epstein Barr virus[23][24] Plaquenil
TLR10 intracellular vesicles

Infection[edit | edit source]

Coxsackie B4 triggers TLR4 on human pancreatic cells[18], TLR4 knock-out mice infected with Coxsackie B3 showed reduced myocarditis and viral replication.[17]

Genetics[edit | edit source]

TLR polymorphisms occur even within a species, and can significantly affect an individual’s susceptibility to infection and disease caused by a particular microbe.[25]

Pharmacology[edit | edit source]

Drugs known to block TLRs include hydroxychloroquine.

Several drugs that target TLRs are being studied for the treatment of cancer and inflammatory diseases.[26]

Learn more[edit | edit source]

See also[edit | edit source]

References[edit | edit source]

  1. Nie, Li; Cai, Shi-Yu; Shao, Jian-Zhong; Chen, Jiong (2018). "Toll-Like Receptors, Associated Biological Roles, and Signaling Networks in Non-Mammals". Frontiers in Immunology. 9. doi:10.3389/fimmu.2018.01523. ISSN 1664-3224. PMC 6043800. PMID 30034391.
  2. Kemball, Christopher C; Alirezaei, Mehrdad; Whitton, J Lindsay (September 2010). "Type B coxsackieviruses and their interactions with the innate and adaptive immune systems". Future microbiology. 5 (9): 1329–1347. doi:10.2217/fmb.10.101. ISSN 1746-0913. PMC 3045535. PMID 20860480.
  3. 3.0 3.1 Bernardino, Andrea L. F.; Myers, Tereance A.; Alvarez, Xavier; Hasegawa, Atsuhiko; Philipp, Mario T. (October 2008). "Toll-Like Receptors: Insights into Their Possible Role in the Pathogenesis of Lyme Neuroborreliosis". Infection and Immunity. 76 (10): 4385–4395. doi:10.1128/IAI.00394-08. ISSN 0019-9567. PMC 2546821. PMID 18694963.
  4. 4.0 4.1 Rahman, Shusmita; Shering, Maria; Ogden, Nicholas H; Lindsay, Robbin; Badawi, Alaa (May 31, 2016). "Toll-like receptor cascade and gene polymorphism in host–pathogen interaction in Lyme disease". Journal of Inflammation Research. 9: 91–102. doi:10.2147/JIR.S104790. ISSN 1178-7031. PMC 4898433. PMID 27330321.
  5. 5.0 5.1 Singh, S.K.; Girschick, H.J. (August 2006). "Toll-like receptors in Borrelia burgdorferi-induced inflammation". Clinical Microbiology and Infection. 12 (8): 705–717. doi:10.1111/j.1469-0691.2006.01440.x.
  6. 6.0 6.1 Joosten, Leo A. B.; Netea, Mihai G.; Meer, Jos W. M. van der; Kullberg, Bart-Jan; Adema, Gosse J.; Sturm, Patrick; Hofstede, Hadewych ter; Oosting, Marije (October 5, 2011). "TLR1/TLR2 Heterodimers Play an Important Role in the Recognition of Borrelia Spirochetes". PLOS ONE. 6 (10): e25998. doi:10.1371/journal.pone.0025998. ISSN 1932-6203. PMC 3187844. PMID 21998742.
  7. Strle, Klemen; Shin, Junghee J.; Glickstein, Lisa J.; Steere, Allen C. (May 2012). "Association of a Toll-like receptor 1 polymorphism with heightened Th1 inflammatory responses and antibiotic-refractory Lyme arthritis". Arthritis and Rheumatism. 64 (5): 1497–1507. doi:10.1002/art.34383. ISSN 1529-0131. PMC 3338893. PMID 22246581.
  8. 8.0 8.1 West, John A.; Gregory, Sean M.; Damania, Blossom (October 8, 2012). "Toll-like receptor sensing of human herpesvirus infection". Frontiers in Cellular and Infection Microbiology. 2. doi:10.3389/fcimb.2012.00122. ISSN 2235-2988. PMC 3465860. PMID 23061052.
  9. 9.0 9.1 Gershon, Anne A.; Gershon, Michael D.; Breuer, Judith; Levin, Myron J.; Oaklander, Anne Louise; Griffiths, Paul D. (May 2010). "Advances in the understanding of the pathogenesis and epidemiology of herpes zoster". Journal of Clinical Virology: The Official Publication of the Pan American Society for Clinical Virology. 48 (Suppl 1): S2–7. doi:10.1016/S1386-6532(10)70002-0. ISSN 1873-5967. PMC 5391040. PMID 20510263.
  10. Compton, Teresa; Kurt-Jones, Evelyn A.; Boehme, Karl W.; Belko, John; Latz, Eicke; Golenbock, Douglas T.; Finberg, Robert W. (April 2003). "Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2". Journal of Virology. 77 (8): 4588–4596. ISSN 0022-538X. PMID 12663765.
  11. Gaudreault, Eric; Fiola, Stéphanie; Olivier, Martin; Gosselin, Jean (August 2007). "Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2". Journal of Virology. 81 (15): 8016–8024. doi:10.1128/JVI.00403-07. ISSN 0022-538X. PMC 1951286. PMID 17522215.
  12. 12.0 12.1 Chen, Xinpu; Chenna, Venugopal; Maitra, Anirban; Devaraj, Sridevi (April 1, 2014). "Nanocurcumin attenuates inflammation by decreasing Toll-like receptor 2 and 4 expression and activity and promoting an anti-inflammatory macrophage phenotype (830.22)". The FASEB Journal. 28 (1_supplement): 830.22. doi:10.1096/fasebj.28.1_supplement.830.22. ISSN 0892-6638.
  13. Negishi, Hideo; Osawa, Tomoko; Ogami, Kentaro; Ouyang, Xinshou; Sakaguchi, Shinya; Koshiba, Ryuji; Yanai, Hideyuki; Seko, Yoshinori; Shitara, Hiroshi (December 23, 2008). "A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity". Proceedings of the National Academy of Sciences of the United States of America. 105 (51): 20446–20451. doi:10.1073/pnas.0810372105. ISSN 1091-6490. PMC 2629334. PMID 19074283.
  14. Guo, Yiqi; Audry, Magali; Ciancanelli, Michael; Alsina, Laia; Azevedo, Joana; Herman, Melina; Anguiano, Esperanza; Sancho-Shimizu, Vanessa; Lorenzo, Lazaro (September 26, 2011). "Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity". The Journal of Experimental Medicine. 208 (10): 2083–2098. doi:10.1084/jem.20101568. ISSN 1540-9538. PMC 3182056. PMID 21911422.
  16. 16.0 16.1 Doan, Thao; Melvold, Roger; Viselli, Susan; Valtenbaugh, Carl (August 28, 2012). Immunology. Lippincott Williams & Wilkins. ISBN 9781451109375.
  17. 17.0 17.1 17.2 Fairweather, DeLisa; Yusung, Susan; Frisancho, Sylvia; Barrett, Masheka; Gatewood, Shannon; Steele, Ronelle; Rose, Noel R. (May 1, 2003). "IL-12 receptor beta 1 and Toll-like receptor 4 increase IL-1 beta- and IL-18-associated myocarditis and coxsackievirus replication". Journal of Immunology (Baltimore, Md.: 1950). 170 (9): 4731–4737. ISSN 0022-1767. PMID 12707353.
  18. 18.0 18.1 Triantafilou, Kathy; Triantafilou, Martha (October 2004). "Coxsackievirus B4-induced cytokine production in pancreatic cells is mediated through toll-like receptor 4". Journal of Virology. 78 (20): 11313–11320. doi:10.1128/JVI.78.20.11313-11320.2004. ISSN 0022-538X. PMID 15452251.
  19. 19.0 19.1 Li, Hui; Li, Xiaoling; Wei, Yun; Tan, Yun; Liu, Xuefeng; Wu, Xinxing (February 13, 2009). "HSV-2 induces TLRs and NF-kappaB-dependent cytokines in cervical epithelial cells". Biochemical and Biophysical Research Communications. 379 (3): 686–690. doi:10.1016/j.bbrc.2008.12.150. ISSN 1090-2104. PMID 19124006.
  20. Pascual, María; Baliño, Pablo; Alfonso-Loeches, Silvia; Aragón, Carlos M.G.; Guerri, Consuelo (June 2011). "Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage". Brain, Behavior, and Immunity. 25: S80–S91. doi:10.1016/j.bbi.2011.02.012.
  21. Fox, Christopher B.; Friede, Martin; Reed, Steven G.; Ireton, Gregory C. (2010). "Synthetic and natural TLR4 agonists as safe and effective vaccine adjuvants". Sub-Cellular Biochemistry. 53: 303–321. doi:10.1007/978-90-481-9078-2_14. ISSN 0306-0225. PMID 20593273.
  23. 23.0 23.1 Martin, Heather J.; Lee, Jae Myun; Walls, Dermot; Hayward, S. Diane (September 2007). "Manipulation of the toll-like receptor 7 signaling pathway by Epstein-Barr virus". Journal of Virology. 81 (18): 9748–9758. doi:10.1128/JVI.01122-07. ISSN 0022-538X. PMC 2045431. PMID 17609264.
  24. van Gent, Michiel; Griffin, Bryan D.; Berkhoff, Eufemia G.; van Leeuwen, Daphne; Boer, Ingrid G.J.; Buisson, Marlyse; Hartgers, Franca C.; Burmeister, Wim P.; Wiertz, Emmanuel J. (February 1, 2011). "EBV lytic-phase protein BGLF5 contributes to TLR9 downregulation during productive infection". Journal of Immunology (Baltimore, Md.: 1950). 186 (3): 1694–1702. doi:10.4049/jimmunol.0903120. ISSN 1550-6606. PMID 21191071.
  25. Berdeli, Afig; Celik, Handan Ak; Ozyürek, Ruhi; Dogrusoz, Buket; Aydin, Hikmet Hakan (July 2005). "TLR-2 gene Arg753Gln polymorphism is strongly associated with acute rheumatic fever in children". Journal of Molecular Medicine (Berlin, Germany). 83 (7): 535–541. doi:10.1007/s00109-005-0677-x. ISSN 0946-2716. PMID 15968536.
  26. O'Neill, Luke A. J.; Parker, Andrew E.; Hennessy, Elizabeth J. (April 2010). "Targeting Toll-like receptors: emerging therapeutics?". Nature Reviews Drug Discovery. 9 (4): 293–307. doi:10.1038/nrd3203. ISSN 1474-1784.