Toll-Like Receptors : Structure, Signaling, and Role in Oral Carcinogenesis and Various Diseases : A Narrative Review
Keywords:
TLRs, Toll-like receptor, Oral carcinogenesis, Signaling
Abstract
Toll-like receptors or TLRs are members of the altered inheritance of PRRs (pattern recognition receptors). They impersonate an important province in linking innate immunity with adaptive immunity. The expression and location of TLRs are controlled as opposed to specialized molecules that elaborate from damaged host cells or pathogens. Over expression of Toll-like receptors can cause agitation of immune homeostasis and mark up the chance of autoimmune and inflammatory diseases. This review examines existing documents in the literature on toll-like receptors. Several databases, including Pubmed,Science Direct, Scopus, and Google Scholar, were searched for papers. Keywords used in the search are "Toll-like receptors", "TLR signaling", "TLR in disease", "TLR in mouth carcinogenesis".
References
1. Wallet SM, Puri V, Gibson FC. Linkage of Infection to Adverse Systemic Complications: Periodontal Disease, Toll-Like Receptors, and Other Pattern Recognition Systems. Vaccines (Basel). 2018;6(2):21.
2. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol .2003;21(1):335–76.
3. Vidya M, Kumar V, Sejian V, Bagath M, Krishnan G, Bhatta R. Toll-like receptors: significance, ligands, signaling pathways, and functions in mammals. Int Rev Immunol.2018; 37(1):20–36.
4. Bhattacharyya S, Varga J. Endogenous ligands of TLR4 promote unresolving tissue fibrosis: implications for systemic sclerosis and its targeted therapy. Immunol Lett. 2018;195:9–17.
5. Ruysschaert JM, Lonez C. Role of lipid microdomains in TLR-mediated signalling. Biochim Biophys Acta .2015;1848(9):1860–7.
6. Reuven EM, Fink A, Shai Y. Regulation of innate immune responses by transmembrane interactions: lessons from the TLR family. Biochim Biophys Acta.2014) 1838(6):1586–93.
7. Hug H, Mohajeri MH, La GF. Toll-like receptors: regulators of the immune response in the human gut. Nutrients.2018;10(2):203.
8. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4(7):499–511.
9.Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann LA . The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell.1996; 86:973–983
10. Schneider DS, Hudson KL, Lin TY, Anderson KV.Dominant and recessive mutations define functional domains of Toll, a Trans membrane protein required for dorsal-ventral polarity in the Drosophila embryo. Genes Dev.1991; 5: 797–807
11. Wang Y, Song E, Bai B, Vanhoutte PM. Toll-like receptors mediating vascular malfunction: Lessons from receptor subtypes. Pharmacol Ther. 2016; 158:91-100
12. Gauthier MEA, Du Pasquier L, Degnan BM.The genome of the sponge Amphimedon queenslandica provides new perspective into the origin of Toll like and interleukin 1 pathways. Evol Dev.2010; 12:519–533
13. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Nat Immunol.2010;11(5):373–384.
14. Gao W, Xiong Y, Li Q, Yang H.Inhibition of Toll-like receptor signaling as a promising therapy for inflammatory diseases: a journey from molecular to nano therapeutics. Front Physiol.2017;8:508–517
15. Wang YC, Lin S, Yang QW.Toll-like receptors in cerebral ischemic inflammatory injury. J Neuroinflammation.2011;8:134
16. Zhang Y, Liang C. Innate recognition of microbial-derived signals in immunity and inflammation. Sci China Life Sci.2016;59(12):1210–17
17. Yuk JM, Jo EK.Toll-like receptors and innate immunity. J Bacteriol Virol.2011;41(4):225–35
18. Delneste Y, Beauvillain C, Jeannin P.Innate immunity: structure and function of TLRs. Med Sci (Paris).2007;23(1):67–73
19. Burns K, Janssens S, Vercammen E, Tschopp J.Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J Exp Med.2003;197:263–8
20. Mansell A, Brint E, Gould JA, O'Neill LA, Hertzog PJ. Mal interacts with tumor necrosis factor receptor-associated factor (TRAF)-6 to mediate NF-κB activation by Toll-like receptor (TLR)-2 and TLR4. J Biol Chem.2004;279:37227– 30
21. Bernard NJ, O'Neill LA. Mal, more than a bridge to MyD88. IUBMB Life.2013;65: 777–86
22. Bryant CE, Symmons M, Gay NJ. Toll-like receptor signaling through macromolecular protein complexes. Mol Immunol.2015;63:162–5
23. Couillault C, Pujol N, Reboul J, Sabatier L, Guichou JF, Kohara Y, Ewbank JJ.TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nature Immunol.2004;5:488–94
24. McGettrick AF, Brint EK, Palsson-McDermott EM, Rowe DC, Golenbock DT, Gay NJ et al. TRIF-related adapter molecule is phosphorylated by PKCε during Toll-like receptor 4 signaling. Proc Natl Acad Sci.2006;103:9196–201
25. Troutman TD, Hu W, Fulenchek S, Yamazaki T, Kurosaki T, Bazan JF.Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt. Proc Natl Acad Sci.2012;109: 273–8
26. Rock, F.L., Hardiman, G., Timans, J.C., Kastelein, R.A., and Bazan, J.F. A family of human receptors structurally related to Drosophila Toll. Proc. Natl. Acad. Sci. USA.1998;95, 588–593
27. O’Neill, L.A., and Greene, C. Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants. J. Leukoc. Biol.1998;63, 650–7
28. Satake, H., and Sekiguchi, T. Toll-like receptors of deuterostome invertebrates. Front. Immunol.2012;3, 34
29. Imler, J.L., and Hoffmann, J.A.Toll receptors in Drosophila: a family of molecules regulating development and immunity. Curr. Top. Microbiol. Immunol.2002;270, 63–79
30. Randow, F., and Seed, B. (2001). Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability. Nat. Cell Biol.2001;3, 891–6
31. 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 Feb;7(2):156-64.
32. 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 Nov 26;204(12):2963-76
33. Kim, Y.M., Brinkmann, M.M., Paquet, M.E., and Ploegh, H.L. (2008). UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature.2008;452, 234–8
34. Pelka K, Bertheloot D, Reimer E, Phulphagar K, Schmidt SV, Christ A, et al. The Chaperone UNC93B1 Regulates Toll-like Receptor Stability Independently of Endosomal TLR Transport. Immunity. 2018;15;48(5):911-22
35. Hemmi H, Takeuchi O, Kawai T. A Toll-like receptor recognizes bacterial DNA. Nature.2000;408(6813):740–5
36. Hoebe K, Du X, Georgel P.Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature.2003;424(6950):743–8
37. Ayres JS, Schneider DS.Tolerance of infections. Annu Rev Immunol.2012;30: 271–94
38. Murad S. Toll-like receptor 4 in inflammation and angiogenesis: a double edged sword. Front Immunol.2014;5:313
39. Re F, Strominger JL. Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells. J Biol Chem.2011;276:37692–9
40. Sharma N, Akhade AS, Qadri A.Sphingosine-1-phosphate suppresses TLRinduced CXCL8 secretion from human T cells. J Leukoc Biol.2013;93(4):521–8
41. Goulopoulou S, McCarthy CG, Webb RC. Toll-like receptors in the vascular system: sensing the dangers within. Pharmacol Rev.2016;68(1):142–67
42. Takeda K, Georgel P, Janssen E. Toll like receptor and their ligands. Proc Natl Acad Sci.2004;101(10):3516–21
43. Kaiser WJ, Offermann MK.Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif. J Immunol.2005; 174(8):4942–52
44. Tsujimoto H, Ono S, Efron PA, Scumpia PO, Moldawer LL, Mochizuki H. Role of Toll-like receptors in the development of sepsis. Shock.2008;29(3):315–21
45. Golshiri-Isfahani A, Amizadeh M, Arababadi MK. The roles of toll like receptor 3, 7 and 8 in allergic rhinitis pathogenesis. Allergol Immunopathol.2018;S0301-0546(17):30186.
46. Jablonska E and Garley M: TLRs and Bcl-2 family proteins in neutrophils of oral cavity cancer patients. Folia Histochem Cytobiol.2009;47(4): 615-9.
47. Park JH, Yoon HE, Jeon DI, Ahn SG and Yoon JH: Activation of TLR2 and TLR5 did not affect tumor progression of an oral squamous cell carcinoma, YD-10B cells. J Oral Pathol Med.2010; 39(10): 781-5.
48. Min R, Siyi L, Wenjun Y, Shengwen L, Ow A, Lizheng W and Chenping Z: Toll like receptor-9 agonists increase cyclin D1 expression partly through activation of activator protein-1 in human oral squamous cell carcinoma cells. Cancer Sci.2012;103(11): 1938-45.
49. Kauppila JH, Korvala J, Siirila K, Manni M, Makinen LK, Hagstrom J,et al. Toll-like receptor 9 mediates invasion and predicts prognosis in squamous cell carcinoma of the mobile tongue. J Oral Pathol Med.2015;44(8): 514- 7.
50. Kotrashetti VS, Nayak R, Bhat K, Hosmani J and Somannavar P: Immunohistochemical expression of TLR4 and TLR9 in various grades of oral epithelial dysplasia and squamous cell carcinoma, and their roles in tumor progression: a pilot study. Biotech Histochem.2013;88(6): 311-22.
51. Ruan M, Thorn K, Liu S, Li S, Yang W, Zhang C and Zhang C: The secretion of IL-6 by CpG-ODN-treated cancer cells promotes T-cell immune responses partly through the TLR-9/AP-1 pathway in oral squamous cell carcinoma. Int J Oncol.2014;44(6): 2103-10.
52. Makinen LK, Atula T, Hayry V, Jouhi L, Datta N, Lehtonen S, Ahmed A, Makitie AA, Haglund C and Hagstrom J: Predictive role of Toll-like receptors 2, 4, and 9 in oral tongue squamous cell carcinoma. Oral Oncol.2015;51(1): 96-102.
53. Ng LK, Rich AM, Hussaini HM, Thomson WM, Fisher AL, Horne LS and Seymour GJ: Toll-like receptor 2 is present in the microenvironment of oral squamous cell carcinoma. Br J Cancer.2011; 104(3): 460-463.
54 Hussaini HM, Parachuru VP, Seymour GJ and Rich AM: Forkhead box-P3+ regulatory T cells and toll-like receptor 2 coexpression in oral squamous cell carcinoma. Acta Histochem.2017;119(3): 205-10.
55. Han S, Xu W, Wang Z, Qi X, Wang Y, Ni Y,et al. Crosstalk between the HIF-1 and Toll-like receptor/ nuclear factor-ĸB pathways in the oral squamous cell carcinoma microenvironment. Oncotarget.2016;7(25): 37773-89.
56. Park JH, Jeon DI, Yoon HE, Kwon SM, Kim SA, Ahn SG and Yoon JH: Poly:C inhibits cell proliferation and enhances the growth inhibitory effect of paclitaxel in oral squamous cell carcinoma. Acta Odontol Scand.2012;70(3): 241-5.
57. He Z, Deng R, Huang X, Ni Y, Yang X, Wang Z and Hu Q: Lipopolysaccharide enhances OSCC migration by promoting epithelial-mesenchymal transition.2015;J Oral Pathol Med 44(9): 685-92.
58. Zeljic K, Supic G, Jovic N, Kozomara R, Brankovic-Magic M, Obrenovic M and Magic Z: Association of TLR2, TLR3, TLR4 and CD14 genes polymorphisms with oral cancer risk and survival Oral Dis.2014;20(4): 416-24.
59. Omar AA, Korvala J, Haglund C, Virolainen S, Hayry V, Atula T et al. Toll-like receptors -4 and -5 in oral and cutaneous squamous cell carcinomas. J Oral Pathol Med.2015;44(4): 258-65.
60. Ren WH, Zhang LM, Liu HQ, Gao L, Chen C, Qiang C,et al.Protein overexpression of CIRP and TLR4 in oral squamous cell carcinoma: an immunohistochemical and clinical correlation analysis. Med Oncol.2014; 31(8): 120.
61. Grimm M, Munz A, Exarchou A, Polligkeit J and Reinert S: Immunohistochemical detection of Helicobacter pylori without association of TLR5 expression in oral squamous cell carcinoma.
J Oral Pathol Med.2014;43(1): 35-44.
62. Ni YH, Ding L, Zhang DY, Hou YY, Huang X and Hu Q: Distinct expression patterns of Toll-like receptor 7 in tumour cells and fibroblast-like cells in oral squamous cell carcinoma.
Histopathology.2015; 67(5): 730-9.
63. Subramanian S, Tus K, Li QZ, Wang A, Tian XH, Zhou J. A TLR7 translocation accelerates systemic autoimmunity in murine lupus. Proc Natl Acad Sci.2006;103:9970–5.
64. Lyn-Cook BD, Xie C, Oates J, Treadwell E, Word B, Hammons G.Increased expression of Toll-like receptors (TLRs) 7 and 9 and other cytokines in systemic lupus erythematous (SLE) patients: ethnic differences and potential new targets for therapeutic drugs. Mol Immunol. 2014;61:38–43
65. Heijden IM, Wilbrink B, Tchetverikov I.Presence of bacterial DNA and bacterial peptidoglycans in the joints of patients with rheumatoid arthritis and other arthritis’s. Arthritis Rheum.1998; 41(9):S162
66. Huang QQ, Pope RM. Role of Toll like receptors in rheumatoid arthritis. Curr Rheumatol Rep.2009;11(5):357–64
67. Radstake TR, Roelofs MF, Jenniskens YM, Oppers-Walgreen B, van Riel PL, Barrera P. Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by pro-inflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma. Arthritis Rheum.2004; 50(12):3856–65.
68. Do JE, Kwon SY, Park S, Lee ES. Effects of vitamin D on expression of tolllike receptors of monocytes from patients with Behcet’s disease. Rheumatol Oxf Engl.2008;47:840–8
69. Lu X, Xu Q, Bu X, Ma X, Zhang F, Deng Q, Zhang Y, Ding J.Relationship between expression of toll-like receptors 2/4 in dendritic cells and chronic hepatitis B virus infection. Int J Clin Exper Pathol.2014;7(9):6048–55.
70. Isaza-Correa JM, Zheng Liang Z, van den Berg A, Arjan Diepstra A, Lydia VL (2014) Toll-like receptors in the pathogenesis of human B cell malignancies.J Hematol Oncol.2014 7:57.
71. So EY, Ouchi T. The application of toll like receptors for cancer therapy. Int J Biol Sci.2010; 6(7):675–81
72. Zhang YW, Thompson R, Zhang H, Xu H. APP processing in Alzheimer’s disease. Mol Brain.2011;4:3–11
2. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol .2003;21(1):335–76.
3. Vidya M, Kumar V, Sejian V, Bagath M, Krishnan G, Bhatta R. Toll-like receptors: significance, ligands, signaling pathways, and functions in mammals. Int Rev Immunol.2018; 37(1):20–36.
4. Bhattacharyya S, Varga J. Endogenous ligands of TLR4 promote unresolving tissue fibrosis: implications for systemic sclerosis and its targeted therapy. Immunol Lett. 2018;195:9–17.
5. Ruysschaert JM, Lonez C. Role of lipid microdomains in TLR-mediated signalling. Biochim Biophys Acta .2015;1848(9):1860–7.
6. Reuven EM, Fink A, Shai Y. Regulation of innate immune responses by transmembrane interactions: lessons from the TLR family. Biochim Biophys Acta.2014) 1838(6):1586–93.
7. Hug H, Mohajeri MH, La GF. Toll-like receptors: regulators of the immune response in the human gut. Nutrients.2018;10(2):203.
8. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4(7):499–511.
9.Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann LA . The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell.1996; 86:973–983
10. Schneider DS, Hudson KL, Lin TY, Anderson KV.Dominant and recessive mutations define functional domains of Toll, a Trans membrane protein required for dorsal-ventral polarity in the Drosophila embryo. Genes Dev.1991; 5: 797–807
11. Wang Y, Song E, Bai B, Vanhoutte PM. Toll-like receptors mediating vascular malfunction: Lessons from receptor subtypes. Pharmacol Ther. 2016; 158:91-100
12. Gauthier MEA, Du Pasquier L, Degnan BM.The genome of the sponge Amphimedon queenslandica provides new perspective into the origin of Toll like and interleukin 1 pathways. Evol Dev.2010; 12:519–533
13. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Nat Immunol.2010;11(5):373–384.
14. Gao W, Xiong Y, Li Q, Yang H.Inhibition of Toll-like receptor signaling as a promising therapy for inflammatory diseases: a journey from molecular to nano therapeutics. Front Physiol.2017;8:508–517
15. Wang YC, Lin S, Yang QW.Toll-like receptors in cerebral ischemic inflammatory injury. J Neuroinflammation.2011;8:134
16. Zhang Y, Liang C. Innate recognition of microbial-derived signals in immunity and inflammation. Sci China Life Sci.2016;59(12):1210–17
17. Yuk JM, Jo EK.Toll-like receptors and innate immunity. J Bacteriol Virol.2011;41(4):225–35
18. Delneste Y, Beauvillain C, Jeannin P.Innate immunity: structure and function of TLRs. Med Sci (Paris).2007;23(1):67–73
19. Burns K, Janssens S, Vercammen E, Tschopp J.Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J Exp Med.2003;197:263–8
20. Mansell A, Brint E, Gould JA, O'Neill LA, Hertzog PJ. Mal interacts with tumor necrosis factor receptor-associated factor (TRAF)-6 to mediate NF-κB activation by Toll-like receptor (TLR)-2 and TLR4. J Biol Chem.2004;279:37227– 30
21. Bernard NJ, O'Neill LA. Mal, more than a bridge to MyD88. IUBMB Life.2013;65: 777–86
22. Bryant CE, Symmons M, Gay NJ. Toll-like receptor signaling through macromolecular protein complexes. Mol Immunol.2015;63:162–5
23. Couillault C, Pujol N, Reboul J, Sabatier L, Guichou JF, Kohara Y, Ewbank JJ.TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nature Immunol.2004;5:488–94
24. McGettrick AF, Brint EK, Palsson-McDermott EM, Rowe DC, Golenbock DT, Gay NJ et al. TRIF-related adapter molecule is phosphorylated by PKCε during Toll-like receptor 4 signaling. Proc Natl Acad Sci.2006;103:9196–201
25. Troutman TD, Hu W, Fulenchek S, Yamazaki T, Kurosaki T, Bazan JF.Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt. Proc Natl Acad Sci.2012;109: 273–8
26. Rock, F.L., Hardiman, G., Timans, J.C., Kastelein, R.A., and Bazan, J.F. A family of human receptors structurally related to Drosophila Toll. Proc. Natl. Acad. Sci. USA.1998;95, 588–593
27. O’Neill, L.A., and Greene, C. Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants. J. Leukoc. Biol.1998;63, 650–7
28. Satake, H., and Sekiguchi, T. Toll-like receptors of deuterostome invertebrates. Front. Immunol.2012;3, 34
29. Imler, J.L., and Hoffmann, J.A.Toll receptors in Drosophila: a family of molecules regulating development and immunity. Curr. Top. Microbiol. Immunol.2002;270, 63–79
30. Randow, F., and Seed, B. (2001). Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability. Nat. Cell Biol.2001;3, 891–6
31. 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 Feb;7(2):156-64.
32. 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 Nov 26;204(12):2963-76
33. Kim, Y.M., Brinkmann, M.M., Paquet, M.E., and Ploegh, H.L. (2008). UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature.2008;452, 234–8
34. Pelka K, Bertheloot D, Reimer E, Phulphagar K, Schmidt SV, Christ A, et al. The Chaperone UNC93B1 Regulates Toll-like Receptor Stability Independently of Endosomal TLR Transport. Immunity. 2018;15;48(5):911-22
35. Hemmi H, Takeuchi O, Kawai T. A Toll-like receptor recognizes bacterial DNA. Nature.2000;408(6813):740–5
36. Hoebe K, Du X, Georgel P.Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature.2003;424(6950):743–8
37. Ayres JS, Schneider DS.Tolerance of infections. Annu Rev Immunol.2012;30: 271–94
38. Murad S. Toll-like receptor 4 in inflammation and angiogenesis: a double edged sword. Front Immunol.2014;5:313
39. Re F, Strominger JL. Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells. J Biol Chem.2011;276:37692–9
40. Sharma N, Akhade AS, Qadri A.Sphingosine-1-phosphate suppresses TLRinduced CXCL8 secretion from human T cells. J Leukoc Biol.2013;93(4):521–8
41. Goulopoulou S, McCarthy CG, Webb RC. Toll-like receptors in the vascular system: sensing the dangers within. Pharmacol Rev.2016;68(1):142–67
42. Takeda K, Georgel P, Janssen E. Toll like receptor and their ligands. Proc Natl Acad Sci.2004;101(10):3516–21
43. Kaiser WJ, Offermann MK.Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif. J Immunol.2005; 174(8):4942–52
44. Tsujimoto H, Ono S, Efron PA, Scumpia PO, Moldawer LL, Mochizuki H. Role of Toll-like receptors in the development of sepsis. Shock.2008;29(3):315–21
45. Golshiri-Isfahani A, Amizadeh M, Arababadi MK. The roles of toll like receptor 3, 7 and 8 in allergic rhinitis pathogenesis. Allergol Immunopathol.2018;S0301-0546(17):30186.
46. Jablonska E and Garley M: TLRs and Bcl-2 family proteins in neutrophils of oral cavity cancer patients. Folia Histochem Cytobiol.2009;47(4): 615-9.
47. Park JH, Yoon HE, Jeon DI, Ahn SG and Yoon JH: Activation of TLR2 and TLR5 did not affect tumor progression of an oral squamous cell carcinoma, YD-10B cells. J Oral Pathol Med.2010; 39(10): 781-5.
48. Min R, Siyi L, Wenjun Y, Shengwen L, Ow A, Lizheng W and Chenping Z: Toll like receptor-9 agonists increase cyclin D1 expression partly through activation of activator protein-1 in human oral squamous cell carcinoma cells. Cancer Sci.2012;103(11): 1938-45.
49. Kauppila JH, Korvala J, Siirila K, Manni M, Makinen LK, Hagstrom J,et al. Toll-like receptor 9 mediates invasion and predicts prognosis in squamous cell carcinoma of the mobile tongue. J Oral Pathol Med.2015;44(8): 514- 7.
50. Kotrashetti VS, Nayak R, Bhat K, Hosmani J and Somannavar P: Immunohistochemical expression of TLR4 and TLR9 in various grades of oral epithelial dysplasia and squamous cell carcinoma, and their roles in tumor progression: a pilot study. Biotech Histochem.2013;88(6): 311-22.
51. Ruan M, Thorn K, Liu S, Li S, Yang W, Zhang C and Zhang C: The secretion of IL-6 by CpG-ODN-treated cancer cells promotes T-cell immune responses partly through the TLR-9/AP-1 pathway in oral squamous cell carcinoma. Int J Oncol.2014;44(6): 2103-10.
52. Makinen LK, Atula T, Hayry V, Jouhi L, Datta N, Lehtonen S, Ahmed A, Makitie AA, Haglund C and Hagstrom J: Predictive role of Toll-like receptors 2, 4, and 9 in oral tongue squamous cell carcinoma. Oral Oncol.2015;51(1): 96-102.
53. Ng LK, Rich AM, Hussaini HM, Thomson WM, Fisher AL, Horne LS and Seymour GJ: Toll-like receptor 2 is present in the microenvironment of oral squamous cell carcinoma. Br J Cancer.2011; 104(3): 460-463.
54 Hussaini HM, Parachuru VP, Seymour GJ and Rich AM: Forkhead box-P3+ regulatory T cells and toll-like receptor 2 coexpression in oral squamous cell carcinoma. Acta Histochem.2017;119(3): 205-10.
55. Han S, Xu W, Wang Z, Qi X, Wang Y, Ni Y,et al. Crosstalk between the HIF-1 and Toll-like receptor/ nuclear factor-ĸB pathways in the oral squamous cell carcinoma microenvironment. Oncotarget.2016;7(25): 37773-89.
56. Park JH, Jeon DI, Yoon HE, Kwon SM, Kim SA, Ahn SG and Yoon JH: Poly:C inhibits cell proliferation and enhances the growth inhibitory effect of paclitaxel in oral squamous cell carcinoma. Acta Odontol Scand.2012;70(3): 241-5.
57. He Z, Deng R, Huang X, Ni Y, Yang X, Wang Z and Hu Q: Lipopolysaccharide enhances OSCC migration by promoting epithelial-mesenchymal transition.2015;J Oral Pathol Med 44(9): 685-92.
58. Zeljic K, Supic G, Jovic N, Kozomara R, Brankovic-Magic M, Obrenovic M and Magic Z: Association of TLR2, TLR3, TLR4 and CD14 genes polymorphisms with oral cancer risk and survival Oral Dis.2014;20(4): 416-24.
59. Omar AA, Korvala J, Haglund C, Virolainen S, Hayry V, Atula T et al. Toll-like receptors -4 and -5 in oral and cutaneous squamous cell carcinomas. J Oral Pathol Med.2015;44(4): 258-65.
60. Ren WH, Zhang LM, Liu HQ, Gao L, Chen C, Qiang C,et al.Protein overexpression of CIRP and TLR4 in oral squamous cell carcinoma: an immunohistochemical and clinical correlation analysis. Med Oncol.2014; 31(8): 120.
61. Grimm M, Munz A, Exarchou A, Polligkeit J and Reinert S: Immunohistochemical detection of Helicobacter pylori without association of TLR5 expression in oral squamous cell carcinoma.
J Oral Pathol Med.2014;43(1): 35-44.
62. Ni YH, Ding L, Zhang DY, Hou YY, Huang X and Hu Q: Distinct expression patterns of Toll-like receptor 7 in tumour cells and fibroblast-like cells in oral squamous cell carcinoma.
Histopathology.2015; 67(5): 730-9.
63. Subramanian S, Tus K, Li QZ, Wang A, Tian XH, Zhou J. A TLR7 translocation accelerates systemic autoimmunity in murine lupus. Proc Natl Acad Sci.2006;103:9970–5.
64. Lyn-Cook BD, Xie C, Oates J, Treadwell E, Word B, Hammons G.Increased expression of Toll-like receptors (TLRs) 7 and 9 and other cytokines in systemic lupus erythematous (SLE) patients: ethnic differences and potential new targets for therapeutic drugs. Mol Immunol. 2014;61:38–43
65. Heijden IM, Wilbrink B, Tchetverikov I.Presence of bacterial DNA and bacterial peptidoglycans in the joints of patients with rheumatoid arthritis and other arthritis’s. Arthritis Rheum.1998; 41(9):S162
66. Huang QQ, Pope RM. Role of Toll like receptors in rheumatoid arthritis. Curr Rheumatol Rep.2009;11(5):357–64
67. Radstake TR, Roelofs MF, Jenniskens YM, Oppers-Walgreen B, van Riel PL, Barrera P. Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by pro-inflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma. Arthritis Rheum.2004; 50(12):3856–65.
68. Do JE, Kwon SY, Park S, Lee ES. Effects of vitamin D on expression of tolllike receptors of monocytes from patients with Behcet’s disease. Rheumatol Oxf Engl.2008;47:840–8
69. Lu X, Xu Q, Bu X, Ma X, Zhang F, Deng Q, Zhang Y, Ding J.Relationship between expression of toll-like receptors 2/4 in dendritic cells and chronic hepatitis B virus infection. Int J Clin Exper Pathol.2014;7(9):6048–55.
70. Isaza-Correa JM, Zheng Liang Z, van den Berg A, Arjan Diepstra A, Lydia VL (2014) Toll-like receptors in the pathogenesis of human B cell malignancies.J Hematol Oncol.2014 7:57.
71. So EY, Ouchi T. The application of toll like receptors for cancer therapy. Int J Biol Sci.2010; 6(7):675–81
72. Zhang YW, Thompson R, Zhang H, Xu H. APP processing in Alzheimer’s disease. Mol Brain.2011;4:3–11
Published
2025-07-11
How to Cite
HIMANSHU SINGH, GOYAL, A., SHARMA, S., ROY, R., GAURAV PRATAP SINGH, & VAISHALI MALIK. (2025). Toll-Like Receptors : Structure, Signaling, and Role in Oral Carcinogenesis and Various Diseases : A Narrative Review. UNIVERSITY JOURNAL OF DENTAL SCIENCES, 11(2). https://doi.org/10.21276/ujds.2025.v11.i2.18
Section
Review Article
