Advertisement

Microglia in the Outer Retina and Their Relevance to Pathogenesis of Age-Related Macular Degeneration

  • Wenxin Ma
  • Lian Zhao
  • Wai T. WongEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)

Abstract

Age-related macular degeneration (AMD), the largest cause of legal blindness in the elderly in the Western world, is a disease whose pathogenesis is incompletely understood and for which therapeutic challenges remain. The etiology of AMD is thought to involve chronic neuroinflammation of the retina but the details of relevant cellular mechanisms are still not fully understood. Retinal microglia are the primary resident immune cell in the retina and are normally absent from the outer retina, the locus of AMD. Their migration and infiltration into the outer retina under conditions of advanced age and disease implicate their involvement in the neuroinflammatory etiology of AMD. We propose that interactions between microglia and RPE cells in the subretinal space result in significant alterations in the structure and physiology of RPE cells that in turn transforms the environment of the retinochoroidal interface into one conducive for the progression and advancement of AMD. In particular, microglia induce RPE alterations that result in a more chemoattractive, pro-inflammatory, and pro-angiogenic environment that increases the recruitment and activation of immune cells and fosters the growth of neovascular vessels into the retina. Microglia-to-RPE influences may represent a cell–cell interaction that may be targeted for therapeutic strategies to treat and/or prevent AMD.

Keywords

Microglia Retinal pigment epithelium Age-related macular degeneration Inflammation Cell–cell interactions Angiogenesis Cytokines Chemokines 

References

  1. Augustin AJ, Kirchhof J (2009) Inflammation and the pathogenesis of age-related macular degeneration. Expert Opin Ther Targets 13:641–651PubMedCrossRefGoogle Scholar
  2. Brown DR (2009) Role of microglia in age-related changes to the nervous system. ScientificWorld Journal 9:1061–1071PubMedCrossRefGoogle Scholar
  3. Cohen SY, Dubois L, Tadayoni R et al (2007) Prevalence of reticular pseudodrusen in age-related macular degeneration with newly diagnosed choroidal neovascularisation. Br J Ophthalmol 91:354–359PubMedCrossRefGoogle Scholar
  4. Combadiere C, Feumi C, Raoul W et al (2007) CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J Clin Invest 117:2920–2928PubMedCrossRefGoogle Scholar
  5. Donoso LA, Kim D, Frost A et al (2006) The role of inflammation in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 51:137–152PubMedCrossRefGoogle Scholar
  6. Ferris FL, Davis MD, Clemons TE et al (2005) A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol 123:1570–1574PubMedCrossRefGoogle Scholar
  7. Friedman DS, O’Colmain BJ, Munoz B et al (2004) Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 122:564–572PubMedCrossRefGoogle Scholar
  8. Green WR (1999) Histopathology of age-related macular degeneration. Mol Vis 5:27PubMedGoogle Scholar
  9. Green WR, Key SN, 3 rd (1977) Senile macular degeneration: a histopathologic study. Trans Am Ophthalmol Soc 75:180–254PubMedGoogle Scholar
  10. Gupta N, Brown KE, Milam AH (2003) Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration. Exp Eye Res 76:463–471PubMedCrossRefGoogle Scholar
  11. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394PubMedCrossRefGoogle Scholar
  12. Holtkamp GM, Kijlstra A, Peek R et al (2001) Retinal pigment epithelium-immune system interactions: cytokine production and cytokine-induced changes. Prog Retin Eye Res 20:29–48PubMedCrossRefGoogle Scholar
  13. Klein R, Klein BE, Jensen SC et al (1997) The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 104:7–21PubMedGoogle Scholar
  14. Lee JE, Liang KJ, Fariss RN et al (2008) Ex vivo dynamic imaging of retinal microglia using time-lapse confocal microscopy. Invest Ophthalmol Vis Sci 49:4169–4176PubMedCrossRefGoogle Scholar
  15. Lucin KM, Wyss-Coray T (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64:110–122PubMedCrossRefGoogle Scholar
  16. Ma W, Zhao L, Fontainhas AM et al (2009) Microglia in the mouse retina alter the structure and function of retinal pigmented epithelial cells: a potential cellular interaction relevant to AMD. PLoS One 4:e7945PubMedCrossRefGoogle Scholar
  17. Mousa SA, Mousa SS (2010) Current status of vascular endothelial growth factor inhibition in age-related macular degeneration. BioDrugs 24:183–194PubMedCrossRefGoogle Scholar
  18. Mousa SA, Mousa SS (2010) Current status of vascular endothelial growth factor inhibition in age-related macular degeneration. BioDrugs 24:183–194PubMedCrossRefGoogle Scholar
  19. Provis JM, Diaz CM, Penfold PL (1996) Microglia in humanz retina: a heterogeneous population with distinct ontogenies. Perspect Dev Neurobiol 3:213–222PubMedGoogle Scholar
  20. Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145PubMedCrossRefGoogle Scholar
  21. Rudolf M, Malek G, Messinger JD et al (2008) Sub-retinal drusenoid deposits in human retina: organization and composition. Exp Eye Res 87:402–408PubMedCrossRefGoogle Scholar
  22. Santos AM, Calvente R, Tassi M et al (2008) Embryonic and postnatal development of microglial cells in the mouse retina. J Comp Neurol 506:224–239PubMedCrossRefGoogle Scholar
  23. Sarks JP, Sarks SH, Killingsworth MC (1988) Evolution of geographic atrophy of the retinal pigment epithelium. Eye 2 ( Pt 5):552–577PubMedCrossRefGoogle Scholar
  24. Streilein JW, Ma N, Wenkel H et al (2002) Immunobiology and privilege of neuronal retina and pigment epithelium transplants. Vision Res 42:487–495PubMedCrossRefGoogle Scholar
  25. Tuo J, Bojanowski CM, Zhou M et al (2007) Murine ccl2/cx3cr1 deficiency results in retinal lesions mimicking human age-related macular degeneration. Invest Ophthalmol Vis Sci 48:3827–3836PubMedCrossRefGoogle Scholar
  26. Xu H, Chen M, Forrester JV (2009) Para-inflammation in the aging retina. Prog Retin Eye Res 28:348–368PubMedCrossRefGoogle Scholar
  27. Xu H, Chen M, Manivannan A et al (2008) Age-dependent accumulation of lipofuscin in perivascular and subretinal microglia in experimental mice. Aging Cell 7:58–68PubMedCrossRefGoogle Scholar
  28. Zarbin MA (2004) Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 122:598–614PubMedCrossRefGoogle Scholar
  29. Zarbin MA, Rosenfeld PJ (2010) Pathway-based therapies for age-related macular degeneration: an integrated survey of emerging treatment alternatives. Retina 30:1350–1367PubMedCrossRefGoogle Scholar
  30. Zweifel SA, Spaide RF, Curcio CA et al (2010a) Reticular pseudodrusen are subretinal drusenoid deposits. Ophthalmology 117:303–312 e301Google Scholar
  31. Zweifel SA, Imamura Y, Spaide TC et al (2010b) Prevalence and significance of subretinal drusenoid deposits (reticular pseudodrusen) in age-related macular degeneration. Ophthalmology 117:1775–1781PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Unit on Neuron–Glia Interactions in Retinal DiseaseNational Eye InstituteBethesdaUSA

Personalised recommendations