A Window to Innate Neuroimmunity: Toll-Like Receptor-Mediated Cell Responses in the Retina

Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)

Abstract

The retina and its supporting cellular architecture are a valuable biologic system to study neurocytotoxic responses that may reveal important pathways in both retinal and neural degenerative diseases. The innate immune pathway mediated by toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA. TLR3 is found both on the cell surface and in endosomes of multiple retinal cell types. Here, we briefly review critical TLR3 signaling pathways and explore the role of receptor activation in neuroimmunity, age-related macular degeneration, and RNA-based drugs.

Keywords

Macular degeneration Innate immunity Toll-like receptor Apoptosis Double-stranded RNA Short interfering RNA Angiogenesis Choroidal neovascularization Caspase 

References

  1. Alexopoulou L, Holt AC, Medzhitov R et al (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732–738PubMedCrossRefGoogle Scholar
  2. Ashikari M, Tokoro M, Itaya M et al (2010) Suppression of laser-induced choroidal neovascularization by nontargeted siRNA. Invest Ophthalmol Vis Sci 51:3820–3824PubMedCrossRefGoogle Scholar
  3. Balachandran S, Thomas E, Barber GN (2004) A FADD-dependent innate immune mechanism in mammalian cells. Nature 432:401–405PubMedCrossRefGoogle Scholar
  4. Berge M, Bonnin P, Sulpice E et al (2010) Small Interfering RNAs Induce Target-Independent Inhibition of Tumor Growth and Vasculature Remodeling in a Mouse Model of Hepatocellular Carcinoma. Am J PatholGoogle Scholar
  5. Cameron JS, Alexopoulou L, Sloane JA et al (2007) Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals. J Neurosci 27:13033–13041PubMedCrossRefGoogle Scholar
  6. Chang CI, Yoo JW, Hong SW et al (2009) Asymmetric shorter-duplex siRNA structures trigger efficient gene silencing with reduced nonspecific effects. Mol Ther 17:725–732PubMedCrossRefGoogle Scholar
  7. Cho WG, Albuquerque RJ, Kleinman ME et al (2009a) Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth. Proc Natl Acad Sci U S A 106:7137–7142PubMedCrossRefGoogle Scholar
  8. Cho Y, Wang JJ, Chew EY et al (2009b) Toll-like receptor polymorphisms and age-related macular degeneration: replication in three case-control samples. Invest Ophthalmol Vis Sci 50:5614–5618PubMedCrossRefGoogle Scholar
  9. Field R, Campion S, Warren C et al (2010) Systemic challenge with the TLR3 agonist poly I:C induces amplified IFNalpha/beta and IL-1beta responses in the diseased brain and exacerbates chronic neurodegeneration. Brain Behav Immun 24:996–1007PubMedCrossRefGoogle Scholar
  10. Gu L, Chen H, Tuo J et al (2010) Inhibition of experimental choroidal neovascularization in mice by anti-VEGFA/VEGFR2 or non-specific siRNA. Exp Eye Res 91:433–439PubMedCrossRefGoogle Scholar
  11. Hoebe K, Janssen EM, Kim SO et al (2003) Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways. Nat Immunol 4:1223–1229PubMedCrossRefGoogle Scholar
  12. Jack CS, Arbour N, Manusow J et al (2005) TLR signaling tailors innate immune responses in human microglia and astrocytes. J Immunol 175:4320–4330PubMedGoogle Scholar
  13. Kariko K, Bhuyan P, Capodici J et al (2004) Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3. J Immunol 172:6545–6549PubMedGoogle Scholar
  14. Klein ML, Ferris FL, 3 rd, Francis PJ et al (2010) Progression of geographic atrophy and genotype in age-related macular degeneration. Ophthalmology 117:1554–1559, 1559 e1551Google Scholar
  15. Kleinman ME, Yamada K, Takeda A et al (2008) Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452:591–597PubMedCrossRefGoogle Scholar
  16. Kumar MV, Nagineni CN, Chin MS et al (2004) Innate immunity in the retina: Toll-like receptor (TLR) signaling in human retinal pigment epithelial cells. J Neuroimmunol 153:7–15PubMedCrossRefGoogle Scholar
  17. Lathia JD, Okun E, Tang SC et al (2008) Toll-like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation. J Neurosci 28:13978–13984PubMedCrossRefGoogle Scholar
  18. Margolis TP, Lietman T, Strauss E (2004) Infectious agents and ARMD: a connection? Am J Ophthalmol 138:468–470PubMedCrossRefGoogle Scholar
  19. Medzhitov R, Janeway C, Jr. (2000) The Toll receptor family and microbial recognition. Trends Microbiol 8:452–456PubMedCrossRefGoogle Scholar
  20. Meylan E, Burns K, Hofmann K et al (2004) RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat Immunol 5:503–507PubMedCrossRefGoogle Scholar
  21. Oda K, Kitano H (2006) A comprehensive map of the toll-like receptor signaling network. Mol Syst Biol 2:2006 0015PubMedGoogle Scholar
  22. Richardson AJ, Islam FM, Guymer RH et al (2007) A tag-single nucleotide polymorphisms approach to the vascular endothelial growth factor-A gene in age-related macular degeneration. Mol Vis 13:2148–2152PubMedGoogle Scholar
  23. Ringheim GE, Conant K (2004) Neurodegenerative disease and the neuroimmune axis (Alzheimer’s and Parkinson’s disease, and viral infections). Journal of Neuroimmunology 147:43–49PubMedCrossRefGoogle Scholar
  24. Sledz CA, Holko M, de Veer MJ et al (2003) Activation of the interferon system by short-interfering RNAs. Nat Cell Biol 5:834–839PubMedCrossRefGoogle Scholar
  25. Yamamoto M, Sato S, Hemmi H et al (2003) Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301:640–643PubMedCrossRefGoogle Scholar
  26. Yang Z, Stratton C, Francis PJ et al (2008) Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. N Engl J Med 359:1456–1463PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Ophthalmology and Visual SciencesUniversity of Kentucky College of MedicineLexingtonUSA

Personalised recommendations