Toll-like Receptors in Multiple Sclerosis: From Immunobiology to Therapeutics
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Abstract
Toll-like Receptors in Multiple Sclerosis: From Immunobiology to Therapeutics
1. Coles A. Multiple sclerosis: the bare essentials. Pract Neurol. 2009;9(2):118-26.
2. Multiple Sclerosis Australia. Types of MS. MSAustralia.org.au; [Internet].
3. Kasper LH, Shoemaker J. Multiple sclerosis immunology: the healthy immune system vs the MS immune system. Neurology. 2010;74(1 Suppl 1):S2-S8.
4. Chastain EM, Duncan DS, Rodgers JM, Miller SD. The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta. 2011;1812(2):265-74.
5. O'Gorman CM, Broadley SA. Smoking increases the risk of progression in multiple sclerosis: A cohort study in Queensland, Australia. J Neurol Sci. 2016;370:219-23.
6. Zhang SM, Willett WC, Hernán MA, Olek MJ, Ascherio A. Dietary fat in relation to risk of multiple sclerosis among two large cohorts of women. Am J Epidemiol. 2000;152(11):1056-64.
7. Speer G. Impact of vitamin D in neurological diseases and neurorehabilitation: from dementia to multiple sclerosis. Part I: the role of vitamin D in the prevention and treatment of multiple sclerosis. Ideggyogy Sz. 2013;66(9-10):293-303.
8. Thom SR, Bhopale VM, Fisher D, Zhang J, Gimotty P. Delayed neuropathology after carbon monoxide poisoning is immune-mediated. Proc Natl Acad Sci U S A. 2004;101(37):13660-5.
9. Sloka S, Silva C, Pryse-Phillips W, Patten S, Metz L, Yong VW. A quantitative analysis of suspected environmental causes of MS. Can J Neurol Sci. 2011;38(1):98-105.
10. Fujinami RS, von Herrath MG, Christen U, Whitton JL. Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev. 2006;19(1):80-94.
11. Modglin L. Multiple sclerosis statistics 2022. SingleCare; 2022 [Internet].
12. Tobin O. Multiple Sclerosis - Diagnosis and Treatment. Mayo Clinic; 2022 [Internet].
13. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2(8):675-80.
14. Delneste Y, Beauvillain C, Jeannin P. Innate immunity: structure and function of TLRs. Med Sci (Paris). 2007;23(1):67-73.
15. Schneider DS, Hudson KL, Lin T-Y, Anderson KV. Dominant and recessive mutations define functional domains of Toll, a transmembrane protein required for dorsal-ventral polarity in the Drosophila embryo. Genes Dev. 1991;5(5):797-807.
16. Anderson KV, Bokla L, Nüsslein-Volhard C. Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell. 1985;42(3):791-8.
17. Kawai T, Akira S, editors. TLR signaling. Semin Immunol. 2007; Elsevier.
18. Brennan JJ, Gilmore TD. Evolutionary origins of Toll-like receptor signaling. Mol Biol Evol. 2018;35(7):1576-87.
19. O'Neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol. 2013;13(6):453-60.
20. O'Neill LAJ, Golenbock D, Bowie AG. The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol. 2013;13(6):453-60.
21. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34(5):637-50.
22. Blasius AL, Beutler B. Intracellular toll-like receptors. Immunity. 2010;32(3):305-15.
23. Celhar T, Magalhaes R, Fairhurst AM. TLR7 and TLR9 in SLE: when sensing self goes wrong. Immunol Res. 2012;53(1):58-77.
24. Lee BL, Moon JE, Shu JH, Yuan L, Newman ZR, Schekman R, et al. UNC93B1 mediates differential trafficking of endosomal TLRs. eLife. 2013;2:e00291.
25. Tabeta K, Hoebe K, Janssen EM, Du X, Georgel P, Crozat K, et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat Immunol. 2006;7(2):156-64.
26. Takahashi K, Shibata T, Akashi-Takamura S, Kiyokawa T, Wakabayashi Y, Tanimura N, et al. A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses. J Exp Med. 2007;204(12):2963-76.
27. Fukui R, Saitoh S, Matsumoto F, Kozuka-Hata H, Oyama M, Tabeta K, et al. Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA-but against RNA-sensing. J Exp Med. 2009;206(6):1339-50.
28. Garcia-Cattaneo A, Gobert FX, Müller M, Toscano F, Flores M, Lescure A, et al. Cleavage of Toll-like receptor 3 by cathepsins B and H is essential for signaling. Proc Natl Acad Sci U S A. 2012;109(23):9053-8.
29. Park B, Brinkmann MM, Spooner E, Lee CC, Kim YM, Ploegh HL. Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nat Immunol. 2008;9(12):1407-14.
30. Majewska M, Szczepanik M. The role of Toll-like receptors (TLR) in innate and adaptive immune responses and their function in immune response regulation. Postepy Hig Med Dosw (Online). 2006;60:52-63.
31. Takemura N, Kawasaki T, Kunisawa J, Sato S, Lamichhane A, Kobiyama K, et al. Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome. Nat Commun. 2014;5(1):1-15.
32. Bernard JJ, Cowing-Zitron C, Nakatsuji T, Muehleisen B, Muto J, Borkowski AW, et al. Ultraviolet radiation damages self noncoding RNA and is detected by TLR3. Nat Med. 2012;18(8):1286-90.
33. Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317(5844):1522-7.
34. Akira S. Pathogen recognition and immune system. Cell. 2006;124(4):783-801.
35. Mancuso G, Gambuzza M, Midiri A, Biondo C, Papasergi S, Akira S, et al. Bacterial recognition by TLR7 in the lysosomes of conventional dendritic cells. Nat Immunol. 2009;10(6):587-94.
36. Guiducci C, Gong M, Cepika AM, Xu Z, Tripodo C, Bennett L, et al. RNA recognition by human TLR8 can lead to autoimmune inflammation. J Exp Med. 2013;210(13):2903-19.
37. Coban C, Igari Y, Yagi M, Reimer T, Koyama S, Aoshi T, et al. Immunogenicity of whole-parasite vaccines against Plasmodium falciparum involves malarial hemozoin and host TLR9. Cell Host Microbe. 2010;7(1):50-61.
38. Regan T, Nally K, Carmody R, Houston A, Shanahan F, MacSharry J, et al. Identification of TLR10 as a key mediator of the inflammatory response to Listeria monocytogenes in intestinal epithelial cells and macrophages. J Immunol. 2013;191(12):6084-92.
39. Lee SM, Kok KH, Jaume M, Cheung TK, Yip TF, Lai JC, et al. Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection. Proc Natl Acad Sci U S A. 2014;111(10):3793-8.
40. Mathur R, Oh H, Zhang D, Park SG, Seo J, Koblansky A, et al. A mouse model of Salmonella typhi infection. Cell. 2012;151(3):590-602.
41. Koblansky AA, Jankovic D, Oh H, Hieny S, Sungnak W, Mathur R, et al. Recognition of profilin by Toll-like receptor 12 is critical for host resistance to Toxoplasma gondii. Immunity. 2013;38(1):119-30.
42. Hidmark A, von Saint Paul A, Dalpke AH. Cutting edge: TLR13 is a receptor for bacterial RNA. J Immunol. 2012;189(6):2717-21.
43. Li M, Zhou Y, Feng G, Su SB. The critical role of Toll-like receptor signaling pathways in the induction and progression of autoimmune diseases. Curr Mol Med. 2009;9(3):365-74.
44. Abdollahi-Roodsaz S, Joosten LA, Roelofs MF, Radstake TR, Matera G, Popa C, et al. Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum. 2007;56(9):2957-67.
45. Fischer M, Ehlers M. Toll-like receptors in autoimmunity. Ann N Y Acad Sci. 2008;1143(1):21-34.
46. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744-8.
47. Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, et al. Phenotypic and functional features of human Th17 cells. J Exp Med. 2007;204(8):1849-61.
48. Luger D, Silver PB, Tang J, Cua D, Chen Z, Iwakura Y, et al. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J Exp Med. 2008;205(4):799-810.
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2. Multiple Sclerosis Australia. Types of MS. MSAustralia.org.au; [Internet].
3. Kasper LH, Shoemaker J. Multiple sclerosis immunology: the healthy immune system vs the MS immune system. Neurology. 2010;74(1 Suppl 1):S2-S8.
4. Chastain EM, Duncan DS, Rodgers JM, Miller SD. The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta. 2011;1812(2):265-74.
5. O'Gorman CM, Broadley SA. Smoking increases the risk of progression in multiple sclerosis: A cohort study in Queensland, Australia. J Neurol Sci. 2016;370:219-23.
6. Zhang SM, Willett WC, Hernán MA, Olek MJ, Ascherio A. Dietary fat in relation to risk of multiple sclerosis among two large cohorts of women. Am J Epidemiol. 2000;152(11):1056-64.
7. Speer G. Impact of vitamin D in neurological diseases and neurorehabilitation: from dementia to multiple sclerosis. Part I: the role of vitamin D in the prevention and treatment of multiple sclerosis. Ideggyogy Sz. 2013;66(9-10):293-303.
8. Thom SR, Bhopale VM, Fisher D, Zhang J, Gimotty P. Delayed neuropathology after carbon monoxide poisoning is immune-mediated. Proc Natl Acad Sci U S A. 2004;101(37):13660-5.
9. Sloka S, Silva C, Pryse-Phillips W, Patten S, Metz L, Yong VW. A quantitative analysis of suspected environmental causes of MS. Can J Neurol Sci. 2011;38(1):98-105.
10. Fujinami RS, von Herrath MG, Christen U, Whitton JL. Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev. 2006;19(1):80-94.
11. Modglin L. Multiple sclerosis statistics 2022. SingleCare; 2022 [Internet].
12. Tobin O. Multiple Sclerosis - Diagnosis and Treatment. Mayo Clinic; 2022 [Internet].
13. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2(8):675-80.
14. Delneste Y, Beauvillain C, Jeannin P. Innate immunity: structure and function of TLRs. Med Sci (Paris). 2007;23(1):67-73.
15. Schneider DS, Hudson KL, Lin T-Y, Anderson KV. Dominant and recessive mutations define functional domains of Toll, a transmembrane protein required for dorsal-ventral polarity in the Drosophila embryo. Genes Dev. 1991;5(5):797-807.
16. Anderson KV, Bokla L, Nüsslein-Volhard C. Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell. 1985;42(3):791-8.
17. Kawai T, Akira S, editors. TLR signaling. Semin Immunol. 2007; Elsevier.
18. Brennan JJ, Gilmore TD. Evolutionary origins of Toll-like receptor signaling. Mol Biol Evol. 2018;35(7):1576-87.
19. O'Neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol. 2013;13(6):453-60.
20. O'Neill LAJ, Golenbock D, Bowie AG. The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol. 2013;13(6):453-60.
21. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34(5):637-50.
22. Blasius AL, Beutler B. Intracellular toll-like receptors. Immunity. 2010;32(3):305-15.
23. Celhar T, Magalhaes R, Fairhurst AM. TLR7 and TLR9 in SLE: when sensing self goes wrong. Immunol Res. 2012;53(1):58-77.
24. Lee BL, Moon JE, Shu JH, Yuan L, Newman ZR, Schekman R, et al. UNC93B1 mediates differential trafficking of endosomal TLRs. eLife. 2013;2:e00291.
25. Tabeta K, Hoebe K, Janssen EM, Du X, Georgel P, Crozat K, et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat Immunol. 2006;7(2):156-64.
26. Takahashi K, Shibata T, Akashi-Takamura S, Kiyokawa T, Wakabayashi Y, Tanimura N, et al. A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses. J Exp Med. 2007;204(12):2963-76.
27. Fukui R, Saitoh S, Matsumoto F, Kozuka-Hata H, Oyama M, Tabeta K, et al. Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA-but against RNA-sensing. J Exp Med. 2009;206(6):1339-50.
28. Garcia-Cattaneo A, Gobert FX, Müller M, Toscano F, Flores M, Lescure A, et al. Cleavage of Toll-like receptor 3 by cathepsins B and H is essential for signaling. Proc Natl Acad Sci U S A. 2012;109(23):9053-8.
29. Park B, Brinkmann MM, Spooner E, Lee CC, Kim YM, Ploegh HL. Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nat Immunol. 2008;9(12):1407-14.
30. Majewska M, Szczepanik M. The role of Toll-like receptors (TLR) in innate and adaptive immune responses and their function in immune response regulation. Postepy Hig Med Dosw (Online). 2006;60:52-63.
31. Takemura N, Kawasaki T, Kunisawa J, Sato S, Lamichhane A, Kobiyama K, et al. Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome. Nat Commun. 2014;5(1):1-15.
32. Bernard JJ, Cowing-Zitron C, Nakatsuji T, Muehleisen B, Muto J, Borkowski AW, et al. Ultraviolet radiation damages self noncoding RNA and is detected by TLR3. Nat Med. 2012;18(8):1286-90.
33. Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317(5844):1522-7.
34. Akira S. Pathogen recognition and immune system. Cell. 2006;124(4):783-801.
35. Mancuso G, Gambuzza M, Midiri A, Biondo C, Papasergi S, Akira S, et al. Bacterial recognition by TLR7 in the lysosomes of conventional dendritic cells. Nat Immunol. 2009;10(6):587-94.
36. Guiducci C, Gong M, Cepika AM, Xu Z, Tripodo C, Bennett L, et al. RNA recognition by human TLR8 can lead to autoimmune inflammation. J Exp Med. 2013;210(13):2903-19.
37. Coban C, Igari Y, Yagi M, Reimer T, Koyama S, Aoshi T, et al. Immunogenicity of whole-parasite vaccines against Plasmodium falciparum involves malarial hemozoin and host TLR9. Cell Host Microbe. 2010;7(1):50-61.
38. Regan T, Nally K, Carmody R, Houston A, Shanahan F, MacSharry J, et al. Identification of TLR10 as a key mediator of the inflammatory response to Listeria monocytogenes in intestinal epithelial cells and macrophages. J Immunol. 2013;191(12):6084-92.
39. Lee SM, Kok KH, Jaume M, Cheung TK, Yip TF, Lai JC, et al. Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection. Proc Natl Acad Sci U S A. 2014;111(10):3793-8.
40. Mathur R, Oh H, Zhang D, Park SG, Seo J, Koblansky A, et al. A mouse model of Salmonella typhi infection. Cell. 2012;151(3):590-602.
41. Koblansky AA, Jankovic D, Oh H, Hieny S, Sungnak W, Mathur R, et al. Recognition of profilin by Toll-like receptor 12 is critical for host resistance to Toxoplasma gondii. Immunity. 2013;38(1):119-30.
42. Hidmark A, von Saint Paul A, Dalpke AH. Cutting edge: TLR13 is a receptor for bacterial RNA. J Immunol. 2012;189(6):2717-21.
43. Li M, Zhou Y, Feng G, Su SB. The critical role of Toll-like receptor signaling pathways in the induction and progression of autoimmune diseases. Curr Mol Med. 2009;9(3):365-74.
44. Abdollahi-Roodsaz S, Joosten LA, Roelofs MF, Radstake TR, Matera G, Popa C, et al. Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum. 2007;56(9):2957-67.
45. Fischer M, Ehlers M. Toll-like receptors in autoimmunity. Ann N Y Acad Sci. 2008;1143(1):21-34.
46. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744-8.
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| Issue | Vol 8, No 2 (2025); in press | |
| Section | Review Article | |
| DOI | https://doi.org/10.18502/igj.v8i2.18002 | |
| Keywords | ||
| Multiple Sclerosis Toll-Like Receptor TLR Autoimmune Disorder Treatment | ||
| Rights and permissions | |
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Kazemzadeh K, Shobeiri P, Teixeira A. Toll-like Receptors in Multiple Sclerosis: From Immunobiology to Therapeutics. Immunol Genet J. 2025;8(2).
