Skip to main content
SpringerLink
Log in

Does toll-like receptor-3 (TLR-3) have any role in Indian AMD phenotype?

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Age-related macular degeneration (AMD) is a devastating disease that results in irreversible central vision loss. TLRs signaling pathway has been found to play an important role in AMD pathogenesis as evidenced by several studies. The objective of the study was to determine the single nucleotide polymorphism (SNP) changes in TLR3 in North Indian AMD patients. We recruited 176 patients comprising 115 AMD patients and 61 controls. Real time PCR was used to evaluate the SNP changes at rs3775291 locus. Pearson’s χ 2 test was used evaluate association between various groups. No significant association in genotype and allele frequency was found in AMD patients as compared to control. The results suggest that AMD pathology in North Indian AMD patients is not affected by TLR3 signaling but it could be influenced by other genetic or environmental factors unique to North India.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. De Jong PT (2006) Age-related macular degeneration. N Engl J Med 355:1474–1485

    Article  PubMed  Google Scholar 

  2. Gorin MB (2005) A new vision for age-related macular degeneration. Eur J Hum Genet 13:793–794

    Article  PubMed  Google Scholar 

  3. Kumar MV, Nagineni CN, Chin MS, Hooks JJ, Detrick B (2004) Innate immunity in the retina: toll-like receptor (TLR) signaling in human retinal pigment epithelial cells. J Neuroimmunol 153:7–15

    Article  CAS  PubMed  Google Scholar 

  4. Liu L, Botos I, Wang Y, Leonard JN, Shiloach J, Segal DM, Davies DR (2008) Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science 320:379–381

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Van B Jr, Buurman WA, Griffioen AW (2008) Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1). Angiogenesis 11:91–99

    Article  Google Scholar 

  6. Park DW, Baek K, Lee JG, Park YK, Kim JH, Kim JR, Baek SH (2007) Activation of toll-like receptor 4 modulates vascular endothelial growth factor synthesis through prostacyclin-IP signaling. Biochem Biophys Res Commun 362:1090–1095

    Article  CAS  PubMed  Google Scholar 

  7. Ambati J, Ambati BK, Yoo SH, Ianchulev S, Adamis AP (2003) Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv Ophthalmol 48:257–293

    Article  PubMed  Google Scholar 

  8. Donoso LA, Kim D, Frost A, Callahan A, Hageman G (2006) The role of inflammation in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 51:137–152

    Article  PubMed  Google Scholar 

  9. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384

    Article  CAS  PubMed  Google Scholar 

  10. Kleinman ME, Kaneko H, Cho WG, Dridi S, Fowler BJ, Blandford AD, Albuquerque RJ, Hirano Y, Terasaki H, Kondo M, Fujita T, Ambati BK, Tarallo V, Gelfand BD, Bogdanovich S, Baffi JZ, Ambati J (2012) Short-interfering RNAs induce retinal degeneration via TLR3 and IRF3. Mol Ther 20(1):101–108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088

    Article  CAS  PubMed  Google Scholar 

  12. Zhu Y, Liang L, Qian D, Yu H, Yang P, Lei B, Peng H (2013) Increase in peripheral blood mononuclear cell Toll-like receptor 2/3 expression and reactivity to their ligands in a cohort of patients with wet age-related macular degeneration. Mol Vis 19:1826–1833

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Maloney SC, Antecka E, Orellana ME, Fernandes BF, Odashiro AN, Eghtedari M, Burnier MN Jr (2010) Choroidal neovascular membranes express toll-like receptor 3. Ophthalmic Res 44(4):237–241

    Article  CAS  PubMed  Google Scholar 

  14. Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi JZ, Albuquerque RJ, Yamasaki S, Itaya M, Pan Y, Appukuttan B, Gibbs D, Yang Z, Karikó K, Ambati BK, Wilgus TA, DiPietro LA, Sakurai E, Zhang K, Smith JR, Taylor EW, Ambati J (2008) Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452(7187):591–597

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Zareparsi S, Buraczynska M, Branham KE, Shah S, Eng D, Li M, Pawar H, Yashar BM, Moroi SE, Lichter PR, Petty HR, Richards JE, Abecasis GR, Elner VM, Swaroop A (2005) Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. Hum Mol Genet 14:1449–1455

    Article  CAS  PubMed  Google Scholar 

  16. Yang Z, Stratton C, Francis PJ, Kleinman ME, Tan PL, Gibbs D, Tong Z, Chen H, Constantine R, Yang X, Chen Y, Zeng J, Davey L, Ma X, Hau VS, Wang C, Harmon J, Buehler J, Pearson E, Patel S, Kaminoh Y, Watkins S, Luo L, Zabriskie NA, Bernstein PS, Cho W, Schwager A, Hinton DR, Klein ML, Hamon SC, Simmons E, Yu B, Campochiaro B, Sunness JS, Campochiaro P, Jorde L, Parmigiani G, Zack DJ, Katsanis N, Ambati J, Zhang K (2008) Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. N Engl J Med 359:1456–1463

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Cho Y, Wang JJ, Chew EY, Ferris FL 3rd, Mitchell P, Chan CC, Tuo J (2009) Toll-like Receptor Polymorphisms and Age-Related Macular Degeneration: replication in Three Case-Control Samples. IOVS 12:5614–5618

    Google Scholar 

  18. Edwards AO, Chen D, Fridley BL, James KM, Wu Y, Abecasis G, Swaroop A, Othman M, Branham K, Iyengar SK, Sivakumaran TA, Klein R, Klein BE, Tosakulwong N (2008) Toll-like receptor polymorphisms and age-related macular degeneration. Invest Ophthalmol Vis Sci 49:1652–1659

    Article  PubMed  Google Scholar 

  19. Sharma NK, Gupta A, Prabhakar S, Singh R, Sharma S, Anand A (2012) Single nucleotide polymorphism and serum levels of VEGFR2 are associated with age related macular degeneration. Curr Neurovascul Res 9:256–265

    Article  CAS  Google Scholar 

  20. McAllister CS, Lakhdari O, Pineton de Chambrun G, Gareau MG, Broquet A, Lee GH, Shenouda S, Eckmann L, Kagnoff MF (2013) TLR3, TRIF, and caspase 8 determine double-stranded RNA-induced epithelial cell death and survival in vivo. J Immunol 190(1):418–427

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Gordon S (2002) Pattern recognition receptors: doubling up for the innate immune response. Cell 111:927–930

    Article  CAS  PubMed  Google Scholar 

  22. Kariko K, Ni H, Capodici J, Lamphier M, Weissman D (2004) mRNA is an endogenous ligand for toll-like receptor 3. J Biol Chem 279:12542–12550

    Article  CAS  PubMed  Google Scholar 

  23. Bell JK, Botos I, Hall PR, Askins J, Shiloach J, Segal DM, Davies DR (2005) The molecular structure of the toll-like receptor 3 ligand-binding domain. Proc Natl Acad Sci USA 102:10976–10980

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Sun J, Duffy KE, Ranjith-Kumar CT, Xiong J, Lamb RJ, Santos J, Masarapu H, Cunningham M, Holzenburg A, Sarisky RT, Mbow ML, Kao C (2006) Structural and functional analyses of the human toll-like receptor 3. Role of glycosylation. J Biol Chem 281:11144–11151

    Article  CAS  PubMed  Google Scholar 

  25. Choe J, Kelker MS, Wilson IA (2005) Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science 309:581–585

    Article  CAS  PubMed  Google Scholar 

  26. Ranjith-Kumar CT, Miller W, Xiong J, Russell WK, Lamb R, Santos J, Duffy KE, Cleveland L, Park M, Bhardwaj K, Wu Z, Russell DH, Sarisky RT, Mbow ML, Kao CC (2007) Biochemical and functional analyses of the human toll-like receptor 3 ectodomain. J Biol Chem 282:7668–7688

    Article  CAS  PubMed  Google Scholar 

  27. de Bouteiller O, Merck E, Hasan UA, Hubac S, Benguigui B, Trinchieri G, Bates EE, Caux C (2005) Recognition of double stranded RNA by human toll-like receptor 3 and downstream receptor signaling requires multimerization and an acidic pH. J Biol Chem 280:38133–38145

    Article  PubMed  Google Scholar 

  28. Cai Jiyang, Nelson KC, Wu Mei, Sternberg Paul Jr, Jones DP (2000) Oxidative damage and protection of the RPE. Prog Retin Eye Res 19(2):205–221

    Article  CAS  PubMed  Google Scholar 

  29. Scholl HP, Fleckenstein M, Fritsche LG, Schmitz-Valckenberg S, Göbel A, Adrion C, Herold C, Keilhauer CN, Mackensen F, Mössner A, Pauleikhoff D, Weinberger AW, Mansmann U, Holz FG, Becker T, Weber BH (2009) CFH, C3 and ARMS2 are significant risk loci for susceptibility but not for disease progression of geographic atrophy due to AMD. PLoS One 4(10):e7418A

    Article  Google Scholar 

  30. Klein ML, Ferris FL, Francis PJ, Lindblad AS, Chew EY, Hamon SC, Ott J (2010) Progression of geographic atrophy and genotype in age-related macular degeneration. Ophthalmology 117(8):1554–1559

    Article  PubMed Central  PubMed  Google Scholar 

  31. Wörnle M, Merkle M, Wolf A, Ribeiro A, Himmelein S, Kernt M, Kampik A, Eibl-Lindner KH (2011) Inhibition of TLR3-mediated proinflammatory effects by alkylphosphocholines in human retinal pigment epithelial cells. IOVS 52(9):10–6993

    Google Scholar 

  32. Anand A, Sharma NK, Gupta A, Prabhakar S, Sharma SK, Singh R, Gupta PK (2012) Single nucleotide polymorphisms in MCP-1 and Its receptor are associated with the risk of age related macular degeneration. PLoS One 7(11):e49905

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Klettner A, Koinzer S, Meyer T, Roider J (2013) Toll-like receptor 3 activation in retinal pigment epithelium cells-Mitogen-activated protein kinase pathways of cell death and vascular endothelial growth factor secretion. Acta Ophthalmol 91(3):e211–e218

    Article  CAS  PubMed  Google Scholar 

  34. Sharma NK, Gupta A, Prabhakar S, Singh R, Bhatt AK, Anand A (2013) CC chemokine receptor-3 as new target for age-related macular degeneration. Gene 523:106–111

    Article  CAS  PubMed  Google Scholar 

  35. Sharma NK, Prabhakar S, Gupta A, Singh R, Gupta PK, Gupta PK, Anand A (2012) New Biomarker for Neovascular Age-Related Macular Degeneration: eotaxin-2. DNA Cell Biol 31:1618–1627

    Article  CAS  PubMed  Google Scholar 

  36. Swaroop A, Chew EY, Rickman CB, Abecasis GR (2009) Unraveling a multifactorial late-onset disease: from genetic susceptibility to disease mechanisms for age-related macular degeneration. Annu Rev Genomics Hum Genet 10:19–43

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Klein R, Klein BE, Moss SE (1998) Relation of smoking to the incidence of age-related maculopathy. The beaver dam eye study. Am J Epidemiol 147:103–110

    Article  CAS  PubMed  Google Scholar 

  38. Seddon JM, Rosner B, Sperduto RD, Yannuzzi L, Haller JA, Blair NP, Willett W (2001) Dietary fat and risk for advanced age-related macular degeneration. Arch Ophthalmol 119:1191–1199

    Article  CAS  PubMed  Google Scholar 

  39. Bollati V, Schwartz J, Wright R, Litonjua A, Tarantini L, Suh H, Sparrow D, Vokonas P, Baccarelli A (2009) Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech Ageing Dev 130:234–239

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Tohgi H, Utsugisawa K, Nagane Y, Yoshimura M, Ukitsu M, Genda Y (1999) Decrease with age in methylcytosines in the promoter region of receptor for advanced glycated end products (RAGE) gene in autopsy human cortex. Brain Res Mol Brain Res 65:124–128

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was carried out at Neuroscience Research Lab, Department of Neurology, Post graduate Institute of Medical Education and Research, Chandigarh, India. We acknowledge ICMR, India for providing funds. We are grateful to Mr. Sumit Rana who carried out the quality assurance of study.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Neuroscience Research Lab, Department of Neurology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

    Neel Kamal Sharma, Kaushal Sharma, Sudesh Prabhakar, Pawan Kumar Gupta & Akshay Anand

  2. Department of Ophthalmology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

    Amod Gupta & Ramandeep Singh

Authors
  1. Neel Kamal Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kaushal Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amod Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sudesh Prabhakar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ramandeep Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pawan Kumar Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akshay Anand
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akshay Anand.

Additional information

Neel Kamal Sharma and Kaushal Sharma have contributed equally to the manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sharma, N.K., Sharma, K., Gupta, A. et al. Does toll-like receptor-3 (TLR-3) have any role in Indian AMD phenotype?. Mol Cell Biochem 393, 1–8 (2014). https://doi.org/10.1007/s11010-014-2040-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-014-2040-4

Keywords

Search

Navigation