World Journal of Dentistry

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VOLUME 10 , ISSUE 5 ( September-October, 2019 ) > List of Articles


Toll-like Receptors: Molecular Microbe Sensors in Periodontium

Pooja R Disale, Sameer Zope, Girish Suragimath, Alluri Siddhartha Varma, Apurva Pisal

Keywords : Cytokines, Inflammatory response, Innate immunity, Pattern-recognition receptors

Citation Information : Disale PR, Zope S, Suragimath G, Varma AS, Pisal A. Toll-like Receptors: Molecular Microbe Sensors in Periodontium. World J Dent 2019; 10 (5):396-401.

DOI: 10.5005/jp-journals-10015-1666

License: CC BY-NC 4.0

Published Online: 01-12-2019

Copyright Statement:  Copyright © 2019; The Author(s).


Aim: This review aims to highlight the emerging role of toll-like receptors (TLRs) in pathogenesis of periodontitis and negative regulation of TLR signaling. Background: Periodontal disease is the common chronic bacterial infection of the supporting structures of the teeth characterized by the tissue destruction. Bacterial plaque stimulates the host inflammatory response. It is now known that the immune response utilizes a family of pattern-recognition receptors (PRRs) called TLR as a tool to trigger an inflammatory response to microbial invasion. The TLRs expressed by epithelial cells of gingiva are constantly stimulated which release cytokines and defensins required for maintenance of oral health. The chronic stimulation of TLRs may leas to the disruption of epithelial barrier and allows microorganisms to enter the underlying connective tissue. This further activates TLRs present on additional cells of the periodontium, i.e., resident and non-resident cells. These TLRs activation may cause host tissue destruction due to an overproduction of proinflammatory cytokines as well other biological mediators. Review results: The electronic databases PubMed, MEDLINE, Cochrane, Scopus and Google Scholar were searched for available data in the present review. A database search yielded a total of 94 articles out of 56 included based on the core data. The results and subsequent conclusions were extracted and reviewed. Conclusion: It may be concluded that TLR signaling is crucial for maintenance of periodontal health as well as initiation and progression of periodontal disease. In spite of this, there are still lacks of information regarding the functional polymorphisms of genes that are involved in the stimulation and regulation of lipopolysaccharide mediated inflammatory processes. Clinical significance: Overactive TLRs might pivot into chronic inflammation, and so targeting TLRs might therefore lead to remission from this chronic inflammation. Therefore, further investigations are necessary to expand our knowledge to understand and develop therapies for major pathologic conditions.

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  1. Medzhitov R, Janeway Jr CA. Innate immunity: the virtues of a nonclonal system of recognition. Cell 1997;91(3):295–298. DOI: 10.1016/S0092-8674(00)80412-2.
  2. Aderem A, Ulevitch R. Toll-like receptors in the induction of the innate immune response. Nature 2000;406(6797):782–787. DOI: 10.1038/35021228.
  3. Hoffmann JA, Kafatos FC, Janeway CA, et al. Phylogenetic perspectives in innate immunity. Science 1999;284(5418):1313–1318. DOI: 10.1126/science.284.5418.1313.
  4. Janeway Jr CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002;20:197–216. DOI: 10.1146/annurev.immunol.20.083001.084359.
  5. Haffajee AD, Socransky SS. Microbial etiological agents of destructive periodontal disease. Periodontol 2000 1994;5(1):78–111. DOI: 10.1111/j.1600-0757.1994.tb00020.x.
  6. Kinane DF, Lappin DF. Immune processes in periodontal disease: a review. Ann Periodontol 2002;7(1):62–71. DOI: 10.1902/annals.2002.7.1.62.
  7. Beklen A, Hukkanen M, Richardson R, et al. Immunohistochemical localization of Toll-like receptors 1-10 in periodontitis. Oral Microbiol Immunol 2008;23(5):425–431. DOI: 10.1111/j.1399-302X.2008.00448.x.
  8. Sugawara Y, Uehara A, Fujimoto Y, et al. Toll-like receptors, NOD1, and NOD2 in oral epithelial cells. J Dent Res 2006;85(6):524–529. DOI: 10.1177/154405910608500609.
  9. Medzhitov R. The innate immune system. In: Paul WE, ed. Fundamental of Immunology. Philadelphia: Lippincott Williams and Wilkins Publishers; 2008. pp. 427–450.
  10. Lemaitre B, Nicolas E, Michaut L, et al. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996;86(6):973–983. DOI: 10.1016/S0092-8674(00)80172-5.
  11. Medzhitov R, Preston-Hurlburt P, Janeway Jr CA. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997;188(6640):394–397. DOI: 10.1038/41131.
  12. Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutation in Tlr4 gene. Science 1998;282(5396):2085–2088. DOI: 10.1126/science.282.5396.2085.
  13. Takeda K, Akira S. Toll like receptors in innate immunity. Int Immunol 2005;17(1):1–14. DOI: 10.1093/intimm/dxh186.
  14. Aderem A, Underhill DM. Mechanisms of phagocytosis in macrophages. Annu Rev Immunol 1999;17:593–623. DOI: 10.1146/annurev.immunol.17.1.593.
  15. Janeway Jr CA. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 1989;54(Pt 1):1–13. DOI: 10.1101/SQB.1989.054.01.003.
  16. Akira S, Hemmi H. Recognition of pathogen associated molecular patterns by TLR family. Immunol Lett 2003;85(2):85–95. DOI: 10.1016/S0165-2478(02)00228-6.
  17. Jin MS, Kim SE, Heo JY, et al. Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 2007;130(6):1071–1082. DOI: 10.1016/j.cell.2007.09.008.
  18. Jin MS, Lee JO. Structure of the Toll-like receptor family and its ligand complexes. Immunity 2008;29(2):182–191. DOI: 10.1016/j.immuni.2008.07.007.
  19. Dunne A, O’Neill LA. The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense. Sci STKE 2003;2003(171):re3. DOI: 10.1126/stke.2003.171.re3.
  20. Akira S, Takeda K. Toll-like receptor signaling. Nat Rev Immunol 2004;4(7):499–511. DOI: 10.1038/nri1391.
  21. Kumar H, Kawai T, Akira S. Pathogen recognition by the innate immune system. Int Rev Immunol 2011;30(1):16–34. DOI: 10.3109/08830185.2010.529976.
  22. Savva A, Roger T. Targeting Toll-like receptors: promising therapeutic strategies for the management of sepsis-associated pathology and infectious diseases. Front Immunol 2013;4:387. DOI: 10.3389/fimmu.2013.00387.
  23. Moore WEC, Moore LVH. The bacteria of periodontal diseases. Periodontol 2000 1994;5(1):66–77. DOI: 10.1111/j.1600-0757.1994.tb00019.x.
  24. Sarah SM, Tamilselvan S, Kamatchiammal S, et al. Expression of Toll-like receptors 2 and 4 in gingivitis and chronic periodontitis. Indian J Dent Res 2006;17(3):114–116. DOI: 10.4103/0970-9290.29879.
  25. Kusumoto Y, Hirano H, Saitoh K, et al. Human gingival epithelial cells produce chemotactic factors interleukin-8 and monocyte chemoattractant protein-1 after stimulation with Porphyromonas gingivalis via toll-like receptor 2. J Periodontol 2004;75(3):370–379. DOI: 10.1902/jop.2004.75.3.370.
  26. Hans M, Hans VM. Toll-like receptors and their dual role in periodontitis: a review. J Oral Sci 2011;53(3):263–271. DOI: 10.2334/josnusd.53.263.
  27. Asai Y, Ohyama Y, Gen K, et al. Bacterial fimbriae and their peptides activate human gingival epithelial cells through Toll-like receptor 2. Infect Immun 2001;69(12):7387–7395. DOI: 10.1128/IAI.69.12.7387-7395.2001.
  28. Takada H, Mihara J, Morisaki I, et al. Induction of interleukin-1 and -6 in human gingival fibroblast cultures stimulated with bacteroides lipopolysaccharides. Infect Immun 1991;59(1):295–301.
  29. Tamura M, Tokuda M, Nagaoka S, et al. Lipopolysaccharides of bacteroides intermedius (Prevotella intermedia) and bacteroides (Porphyromonas) gingivalis induce interleukin-8 gene expression in human gingival fibroblast cultures. Infect Immun 1992;60(11):4932–4937.
  30. Yamazaki K, Ikarashi F, Aoyagi T, et al. Direct and indirect effects of Porphyromonas gingivalis lipopolysaccharide on interleukin-6 production by human gingival fibroblasts. Oral Microbiol Immunol 1992;7(4):218–224. DOI: 10.1111/j.1399-302X.1992.tb00028.x.
  31. Kline KA, Fälker S, Dahlberg S, et al. Bacterial adhesions in host-microbe interactions. Cell Host Microbe 2009;5(6):580–592. DOI: 10.1016/j.chom.2009.05.011.
  32. O’Neill LA. When signaling pathways collide: positive and negative regulation of toll-like receptor signal transduction. Immunity 2008;29(1):12–20. DOI: 10.1016/j.immuni.2008.06.004.
  33. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001;2(8):675–680. DOI: 10.1038/90609.
  34. Doyle S, Vaidya S, O’Connell R, et al. IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 2002;17(3):251–263. DOI: 10.1016/S1074-7613(02)00390-4.
  35. Mariotti A, Mawhinney MG. Endocrinology of sex steroid hormones and cell dynamics in the periodontium. Periodontol 2000 2013;61(1):69–88. DOI: 10.1111/j.1600-0757.2011.00424.x.
  36. Weinberg A, Krisanaprakornkit S, Dale BA. Epithelial antimicrobial peptides: review and significance for oral applications. Crit Rev Oral Biol Med 1998;9(4):399–414. DOI: 10.1177/10454411980090040201.
  37. Han YW, Shi W, Huang GT, et al. Interactions between periodontal bacteria and human oral epithelial cells: fusobacterium nucleatum adheres to and invades epithelial cells. Infect Immun 2000;68(6):3140–3146. DOI: 10.1128/IAI.68.6.3140-3146.2000.
  38. Warner RL, Bhagavathula N, Nerusu KC, et al. Matrix metalloproteinases in acute inflammation: induction of MMP-3 and MMP-9 in fibroblasts and epithelial cells following exposure to proinflammatory mediators in vitro. Exp Mol Pathol 2004;76(3):189–195. DOI: 10.1016/j.yexmp.2004.01.003.
  39. Galdiero M, de l’Ero GC, Marcatili A. Cytokine and adhesion molecule expression in human monocytes and endothelial cells stimulated with bacterial heat shock proteins. Infect Immun 1997;65(2):699–707.
  40. Jiang Y, Mehta CK, Hsu TY, et al. Bacteria induce osteoclastogenesis via an osteoblast-independent pathway. Infect Immun 2002;70(6):3143–3148. DOI: 10.1128/IAI.70.6.3143-3148.2002.
  41. Trevani AS, Chorny A, Salamone G, et al. Bacterial DNA activates human neutrophils by a CpG-independent pathway. Eur J Immunol 2003;33(11):3164–3174. DOI: 10.1002/eji.200324334.
  42. Mori Y, Yoshimura A, Ukai T, et al. Immunohistochemical localization of Toll-like receptors 2 and 4 in gingival tissue from patients with periodontitis. Oral Microbiol Immunol 2003;18(1):54–58. DOI: 10.1034/j.1399-302X.2003.180109.x.
  43. El-Dessouky HF, Ahmed OI. Expression of Toll-like receptors 2 and 4 in periodontal diseases. Egypt J Med Microbiol 2007;16(3):553–559.
  44. Srinivasan M, Kodumudi KN, Galli DM. Aggregatibacter actinomycetemcomitans modulates toll-like receptors 2 and 4 in gingival epithelial cells in experimental periodontitis. J Int Clin Dent Res Organ 2010;2:24–29. DOI: 10.4103/2231-0754.89992.
  45. Kajita K, Honda T, Amanuma R, et al. Quantitative messenger RNA expression of Toll-like receptors and interferon-α1 in gingivitis and periodontitis. Oral Microbiol Immunol 2007;22(6):398–402. DOI: 10.1111/j.1399-302X.2007.00377.x.
  46. Kim PD, Xia-Juan X, Crump KE, et al. Toll-like receptor 9-mediated inflammation triggers alveolar bone loss in experimental murine periodontitis. Infect Immun 2015;83(7):2992–3002. DOI: 10.1128/IAI.00424-15.
  47. Maheaswari R, Sivasankar K, Subbarayan S. Toll gates: an emerging therapeutic target. J Indian Soc Periodontol 2014;18(6):686–692. DOI: 10.4103/0972-124X.147398.
  48. Patra MC, Choi S. Recent progress in the development of Toll-like receptor(TLR) antagonists. Expert Opin Ther Pat 2016;26(6):719–730. DOI: 10.1080/13543776.2016.1185415.
  49. Molteni M, Bosi A, Rossetti C. Natural products with Toll-like receptor 4 antagonist activity. Int J Inflam 2018;2018:2859135. DOI: 10.1155/2018/2859135.
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