Molecular mechanisms of retinal pigment epithelium damage and development of age-related macular degeneration

Acta Ophthalmologica

Volumn 90, Issue 4, 2012, Pages 299-309

  Kinnunen, Kati ^a,b   Petrovski, Goran ^c,d   Moe, Morten C ^e   Berta, András ^d   Kaarniranta, Kai ^a,b  

^a UNIVERSITY OF EASTERN FINLAND   (Finland)

^b KUOPIO UNIVERSITY HOSPITAL   (Finland)

^c UNIVERSITY OF DEBRECEN   (Hungary)

^d UNIVERSITY OF DEBRECEN   (Hungary)

^e ULLEVÅL UNIVERSITY HOSPITAL   (Norway)

Author keywords

drusen; lipofuscin; macular degeneration; retinal pigment epithelium

Indexed keywords

HEAT SHOCK PROTEIN; LIPOFUSCIN; PATTERN RECOGNITION RECEPTOR; PROTEASOME; VASCULOTROPIN;

AGE DISTRIBUTION; ARTERIOSCLEROSIS; AUTOPHAGY; BLOOD RETINA BARRIER; BRUCH MEMBRANE; CHOROID CAPILLARY LAYER; DISEASE CLASSIFICATION; DISEASE COURSE; DRUSEN; ENDOCYTOSIS; FAMILY HISTORY; GENETIC ASSOCIATION; GENETIC PREDISPOSITION; GENOTYPE ENVIRONMENT INTERACTION; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTENSION; INFLAMMATION; INNATE IMMUNITY; MOLECULAR PATHOLOGY; NONHUMAN; OXIDATIVE STRESS; PHAGOCYTOSIS; PHENOTYPE; PHOTORECEPTOR; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN ANALYSIS; PROTEIN DEFECT; PROTEIN DEGRADATION; PROTEIN FOLDING; PROTEIN FUNCTION; RETINA MACULA AGE RELATED DEGENERATION; RETINA PIGMENT EPITHELIOPATHY; REVIEW; RISK FACTOR; SEX DIFFERENCE; SMOKING; SUBRETINAL NEOVASCULARIZATION;

HUMANS; LIPOFUSCIN; LYSOSOMES; MACULAR DEGENERATION; OXIDATIVE STRESS; PHENOTYPE; RETINAL PIGMENT EPITHELIUM;

EID: 84861600073     PISSN: 1755375X     EISSN: 17553768     Source Type: Journal    
DOI: 10.1111/j.1755-3768.2011.02179.x     Document Type: Review

References (176)

1. Achen M, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks A, Alitalo K, &, Stacker S, (1998): Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci USA 95: 548-553.
2. Age-Related Eye Disease Study Research Group (2000): Risk factors associated with age-related macular degeneration: a case-control study in the age-related eye disease study: age-related eye disease study report number 3 Ophthalmology 107: 2224-2232.
3. Akiyama H, Mohamedali KA, E Silva RL, et al., (2005): Vascular targeting of ocular neovascularization with a vascular endothelial growth factor121/gelonin chimeric protein. Mol Pharmacol 68: 1543-1550.
4. Algvere PV, &, Seregard S, (2002): Age-related maculopathy: pathogenetic features and new treatment modalities. Acta Ophthalmol Scand 80: 136-143.
5. 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.
6. Anderson DH, Ozaki S, Nealon M, Neitz J, Mullins RF, Hageman GS, &, Johnson LV, (2001): Local cellular sources of apolipoprotein E in the human retina and retinal pigmented epithelium: implications for the process of drusen formation. Am J Ophthalmol 131: 767-781.
7. Anderson DH, Mullins RF, Hageman GS, &, Johnson LV, (2002): A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 134: 411-431.
8. Arjamaa O, Nikinmaa M, Salminen A, &, Kaarniranta K, (2009): Regulatory role of HIF-1α in the pathogenesis of age-related macular degeneration (AMD). Ageing Res Rev 8: 349-358.
9. Baird PN, Richardson AJ, Robman LD, Dimitrov PN, Tikellis G, McCarty CA, &, Guymer RH, (2006): Apolipoprotein (APOE) gene is associated with progression of age-related macular degeneration (AMD). Hum Mutat 27: 337-342.
10. Barnstable CJ, &, Tombran-Tink J, (2004): Neuroprotective and antiangiogenic actions of PEDF in the eye: molecular targets and therapeutic potential. Prog Retin Eye Res 23: 561-577.
11. Beatty S, Koh H, Phil M, Henson D, &, Boulton M, (2000): The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 45: 115-134.
12. Bergmann M, Schutt F, Holz FG, &, Kopitz J, (2004): Inhibition of the ATP-driven proton pump in RPE lysosomes by the major lipofuscin fluorophore A2-E may contribute to the pathogenesis of age-related macular degeneration. FASEB J 18: 562-564.
13. Bianchi ME, (2007): DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81: 1-5.
14. Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, &, Nawroth PP, (2005): Understanding RAGE, the receptor for advanced glycation end products. J Mol Med 83: 876-886.
15. Bindewald A, Bird AC, Dandekar SS, et al., (2005): Classification of fundus autofluorescence patterns in early age-related macular disease. Invest Ophthalmol Vis Sci 46: 3309-3314.
16. Bjorkoy G, Lamark T, &, Johansen T, (2006): p62/SQSTM1: a missing link between protein aggregates and the autophagy machinery. Autophagy 2: 138-139.
17. Blaauwgeers HGT, Holtkamp GM, Rutten H, et al., (1999): Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris: evidence for a trophic paracrine relation. Am J Pathol 155: 421-428.
18. Boulton M, Dontsov A, Jarvis-Evans J, Ostrovsky M, &, Svistunenko D, (1993): Lipofuscin is a photoinducible free radical generator. J Photochem Photobiol B 19: 201-204.
19. Boyle D, Tien LF, Cooper NG, Shepherd V, &, McLaughlin BJ, (1991): A mannose receptor is involved in retinal phagocytosis. Invest Ophthalmol Vis Sci 32: 1464-1470.
20. Bressler NM, Bressler SB, &, Fine SL, (1988): Age-related macular degeneration. Surv Ophthalmol 32: 375-413.
21. Buchner J, (1996): Supervising the fold: functional principles of molecular chaperones. FASEB J 10: 10-19.
22. Caberoy NB, Maiguel D, Kim Y, &, Li W, (2010): Identification of tubby and tubby-like protein 1 as eat-me signals by phage display. Exp Cell Res 316: 245-257.
23. Carmeliet P, Ferreira V, Breier G, et al., (1996): Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380: 435-439.
24. Chen M, Muckersie E, Forrester JV, &, Xu H, (2010): Immune activation in retinal aging: a gene expression study. Invest Ophthalmol Vis Sci 51: 5888-5896.
25. Ciechanover A, (2005): Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Cell Death Differ 12: 1178-1190.
26. Crabb JW, Miyagi M, Gu X, et al., (2002): Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci USA 99: 14682-14687.
27. Craig EA, Weissman JS, &, Horwich AL, (1994): Heat shock proteins and molecular chaperones: mediators of protein conformation and turnover in the cell. Cell 78: 365-372.
28. Cuervo AM, &, Dice JF, (1996): A receptor for the selective uptake and degradation of proteins by lysosomes. Science 273: 501-503.
29. Decanini A, Nordgaard CL, Feng X, Ferrington DA, &, Olsen TW, (2007): Changes in select redox proteins of the retinal pigment epithelium in age-related macular degeneration. Am J Ophthalmol 143: 607-615.
30. Delori FC, Goger DG, &, Dorey CK, (2001): Age-related accumulation and spatial distribution of lipofuscin in RPE of normal subjects. Invest Ophthalmol Vis Sci 42: 1855-1866.
31. Dewan A, Liu M, Hartman S, et al., (2006): HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314: 989-992.
32. Dice JF, (2007): Chaperone-mediated autophagy. Autophagy 3: 295-299.
33. Dunaief JL, Dentchev T, Ying G, &, Milam AH, (2002): The role of apoptosis in age-related macular degeneration. Arch Ophthalmol 120: 1435-1442.
34. Ebihara N, Chen L, Tokura T, Ushio H, Iwatsu M, &, Murakami A, (2007): Distinct functions between toll-like receptors 3 and 9 in retinal pigment epithelial cells. Ophthalmic Res 39: 155-163.
35. Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, &, Farrer LA, (2005): Complement factor H polymorphism and age-related macular degeneration. Science 308: 421-424.
36. Elner VM, Elner SG, Bian Z, Kindezelskii AL, Yoshida A, &, Petty HR, (2003): RPE CD14 immunohistochemical, genetic, and functional expression. Exp Eye Res 76: 321-331.
37. Elner SG, Petty HR, Elner VM, Yoshida A, Bian Z, Yang D, &, Kindzelskii AL, (2005): TLR4 mediates human retinal pigment epithelial endotoxin binding and cytokine expression. Invest Ophthalmol Vis Sci 46: 4627-4633.
38. Epstein FH, Mitch WE, &, Goldberg AL, (1996): Mechanisms of muscle wasting - the role of the ubiquitin-proteasome pathway. N Engl J Med 335: 1897-1905.
39. Eskelinen E, &, Saftig P, (2009): Autophagy: a lysosomal degradation pathway with a central role in health and disease. Biochim Biophys Acta 1793: 664-673.
40. Ferrara N, Houck KA, Jakeman LB, Winer J, &, Leung DW, (1991): The vascular endothelial growth factor family of polypeptides. J Cell Biochem 47: 211-218.
41. Ferrara N, Gerber H, &, LeCouter J, (2003): The biology of VEGF and its receptors. Nat Med 9: 669-676.
42. Fesus L, Demeny MA, &, Petrovski G, (2011): Autophagy shapes inflammation. Antioxid Redox Signal [Epub ahead of print].
43. Filleur S, Nelius T, de Riese W, &, Kennedy R, (2009): Characterization of PEDF: a multi-functional serpin family protein. J Cell Biochem 106: 769-775.
44. Forrester JV, (2003): Macrophages eyed in macular degeneration. Nat Med 9: 1350-1351.
45. Forrester JV, McMenamin PG, Holthouse I, Lumsden L, &, Liversidge J, (1994): Localization and characterization of major histocompatibility complex class II-positive cells in the posterior segment of the eye: implications for induction of autoimmune uveoretinitis. Invest Ophthalmol Vis Sci 35: 64-77.
46. Forrester JV, Xu H, Kuffova L, Dick AD, &, McMenamin PG, (2010): Dendritic cell physiology and function in the eye. Immunol Rev 234: 282-304.
47. Garcia-Mata R, Bebok Z, Sorscher EJ, &, Sztul ES, (1999): Characterization and dynamics of aggresome formation by a cytosolic GFP-chimera. J Cell Biol 146: 1239-1254.
48. Gille H, Kowalski J, Li B, LeCouter J, Moffat B, Zioncheck TF, Pelletier N, &, Ferrara N, (2001): Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem 276: 3222-3230.
49. Gilmore AP, (2005): Anoikis. Cell Death Differ 12 (Suppl 2): 1473-1477.
50. Green WR, &, Enger C, (2005): Age-related macular degeneration histopathologic studies: the 1992 Lorenz E. Zimmerman Lecture. 1992. Retina 25: 1519-1535.
51. Green WR, &, Key SN 3rd, (2005): Senile macular degeneration: a histopathologic study. 1977. Retina 25: 180-250.
52. Gurne DH, Tso MO, Edward DP, &, Ripps H, (1991): Antiretinal antibodies in serum of patients with age-related macular degeneration. Ophthalmology 98: 602-607.
53. Hafezi F, Marti A, Munz K, &, Reme CE, (1997): Light-induced apoptosis: differential timing in the retina and pigment epithelium. Exp Eye Res 64: 963-970.
54. Hageman GS, &, Mullins RF, (1999): Molecular composition of drusen as related to substructural phenotype. Mol Vis 5: 28.
55. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, &, Mullins RF, (2001): An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 20: 705-732.
56. Hageman GS, Anderson DH, Johnson LV, et al., (2005): A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 102: 7227-7232.
57. Haines JL, Hauser MA, Schmidt S, et al., (2005): Complement factor H variant increases the risk of age-related macular degeneration. Science 308: 419-421.
58. Halle A, Hornung V, Petzold GC, et al., (2008): The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9: 857-865.
59. Hartl FU, (1996): Molecular chaperones in cellular protein folding. Nature 381: 571-579.
60. Hartl FU, &, Hayer-Hartl M, (2002): Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295: 1852-1858.
61. Hershko A, &, Ciechanover A, (1998): The ubiquitin system. Annu Rev Biochem 67: 425-479.
62. Holtkamp GM, Kijlstra A, Peek R, &, de Vos AF, (2001): Retinal pigment epithelium-immune system interactions: cytokine production and cytokine-induced changes. Prog Retin Eye Res 20: 29-48.
63. Holz F, Schutt F, Kopitz J, Eldred G, Kruse F, Volcker H, &, Cantz M, (1999): Inhibition of lysosomal degradative functions in RPE cells by a retinoid component of lipofuscin. Invest Ophthalmol Vis Sci 40: 737-743.
64. Holz FG, Bindewald-Wittich A, Fleckenstein M, Dreyhaupt J, Scholl HP, Schmitz-Valckenberg S, & FAM-Study Group (2007): Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol 143: 463-472.
65. Howes KA, Liu Y, Dunaief JL, Milam A, Frederick JM, Marks A, &, Baehr W, (2004): Receptor for advanced glycation end products and age-related macular degeneration. Invest Ophthalmol Vis Sci 45: 3713-3720.
66. Ikeda Y, Yonemitsu Y, Onimaru M, et al., (2006): The regulation of vascular endothelial growth factors (VEGF-A, -C, and -D) expression in the retinal pigment epithelium. Exp Eye Res 83: 1031-1040.
67. Irschick EU, Sgonc R, Bock G, Wolf H, Fuchs D, Nussbaumer W, Gottinger W, &, Huemer HP, (2004): Retinal pigment epithelial phagocytosis and metabolism differ from those of macrophages. Ophthalmic Res 36: 200-210.
68. Ishibashi T, Murata T, Hangai M, Nagai R, Horiuchi S, Lopez PF, Hinton DR, &, Ryan SJ, (1998): Advanced glycation end products in age-related macular degeneration. Arch Ophthalmol 116: 1629-1632.
69. Izumi-Nagai K, Nagai N, Ozawa Y, et al., (2007): Interleukin-6 receptor-mediated activation of signal transducer and activator of transcription-3 (STAT3) promotes choroidal neovascularization. Am J Pathol 170: 2149-2158.
70. Jager RD, Mieler WF, &, Miller JW, (2008): Age-related macular degeneration. N Engl J Med 358: 2606-2617.
71. Javitt NB, &, Javitt JC, (2009): The retinal oxysterol pathway: a unifying hypothesis for the cause of age-related macular degeneration. Curr Opin Ophthalmol 20: 151-157.
72. Johnson LV, Leitner WP, Staples MK, &, Anderson DH, (2001): Complement activation and inflammatory processes in drusen formation and age related macular degeneration. Exp Eye Res 73: 887-896.
73. Johnston JA, Ward CL, &, Kopito RR, (1998): Aggresomes: a cellular response to misfolded proteins. J Cell Biol 143: 1883-1898.
74. Johnston JA, Illing ME, &, Kopito RR, (2002): Cytoplasmic dynein/dynactin mediates the assembly of aggresomes. Cell Motil Cytoskeleton 53: 26-38.
75. Joukov V, Kaipainen A, Jeltsch M, Pajusola K, Olofsson B, Kumar V, Eriksson U, &, Alitalo K, (1997): Vascular endothelial growth factors VEGF-B and VEGF-C. J Cell Physiol 173: 211-215.
76. Kaarniranta K, (2010): Autophagy-hot topic in AMD. Acta Ophthalmol 88: 387-388.
77. Kaarniranta K, &, Salminen A, (2009): Age-related macular degeneration: activation of innate immunity system via pattern recognition receptors. J Mol Med 87: 117-123.
78. Kaarniranta K, Elo M, Sironen R, Lammi MJ, Goldring MB, Eriksson JE, Sistonen L, &, Helminen HJ, (1998): Hsp70 accumulation in chondrocytic cells exposed to high continuous hydrostatic pressure coincides with mRNA stabilization rather than transcriptional activation. Proc Natl Acad Sci USA 95: 2319-2324.
79. Kaarniranta K, Ryhänen T, Sironen RK, et al., (2005): Geldanamycin activates Hsp70 response and attenuates okadaic acid-induced cytotoxicity in human retinal pigment epithelial cells. Brain Res Mol Brain Res 137: 126-131.
80. Kaarniranta K, Salminen A, Eskelinen E, &, Kopitz J, (2009): Heat shock proteins as gatekeepers of proteolytic pathways-implications for age-related macular degeneration (AMD). Ageing Res Rev 8: 128-139.
81. Kaarniranta K, Hyttinen J, Ryhanen T, Viiri J, Paimela T, Toropainen E, Sorri I, &, Salminen A, (2010): Mechanisms of protein aggregation in the retinal pigment epithelial cells. Front Biosci (Elite Ed) 2: 1374-1384.
82. Kaarniranta K, Salminen A, Haapasalo A, Soininen H, &, Hiltunen M, (2011): Age-Related Macular Degeneration (AMD): Alzheimer's Disease in the Eye? J Alzheimers Dis [Epub ahead of print].
83. Killingsworth MC, Sarks JP, &, Sarks SH, (1990): Macrophages related to Bruch's membrane in age-related macular degeneration. Eye 4 (Pt 4): 613-621.
84. Kim I, Ryan A, Rohan R, Amano S, Agular S, Miller J, &, Adamis A, (1999): Constitutive expression of VEGF, VEGFR-1, and VEGFR-2 in normal eyes. Invest Ophthalmol Vis Sci 40: 2115-2121.
85. Kim PK, Hailey DW, Mullen RT, &, Lippincott-Schwartz J, (2008): Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc Nat Acad Sci USA 105: 20567-20574.
86. Kindzelskii AL, Elner VM, Elner SG, Yang D, Hughes BA, &, Petty HR, (2004): Toll-like receptor 4 (TLR4) of retinal pigment epithelial cells participates in transmembrane signaling in response to photoreceptor outer segments. J Gen Physiol 124: 139-149.
87. Kirkin V, McEwan DG, Novak I, &, Dikic I, (2009): A role for ubiquitin in selective autophagy. Mol Cell 34: 259-269.
88. Klaver CC, Kliffen M, van Duijn CM, Hofman A, Cruts M, Grobbee DE, van Broeckhoven C, &, de Jong PT, (1998): Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet 63: 200-206.
89. Klein R, Klein BEK, &, Moss SE, (1998): Relation of smoking to the incidence of age-related maculopathy: the Beaver Dam Eye Study. Am J Epidemiol 147: 103-110.
90. Klein RJ, Zeiss C, Chew EY, et al., (2005): Complement factor H polymorphism in age-related macular degeneration. Science 308: 385-389.
91. Kopito RR, (2000): Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10: 524-530.
92. Korte GE, Reppucci V, &, Henkind P, (1984): RPE destruction causes choriocapillary atrophy. Invest Ophthalmol Vis Sci 25: 1135-1145.
93. Koto T, Nagai N, Mochimaru H, et al., (2007): Eicosapentaenoic acid is anti-inflammatory in preventing choroidal neovascularization in mice. Invest Ophthalmol Vis Sci 48: 4328-4334.
94. Krohne TU, Stratmann NK, Kopitz J, &, Holz FG, (2010): Effects of lipid peroxidation products on lipofuscinogenesis and autophagy in human retinal pigment epithelial cells. Exp Eye Res 90: 465-471.
95. 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.
96. Kuusisto E, Suuronen T, &, Salminen A, (2001): Ubiquitin-binding protein p62 expression is induced during apoptosis and proteasomal inhibition in neuronal cells. Biochem Biophys Res Commun 280: 223-228.
97. Kuusisto E, Salminen A, &, Alafuzoff I, (2002): Early accumulation of p62 in neurofibrillary tangles in Alzheimer's disease: possible role in tangle formation. Neuropathol Appl Neurobiol 28: 228-237.
98. Lau LI, Chen SJ, Cheng CY, Yen MY, Lee FL, Lin MW, Hsu WM, &, Wei YH, (2006): Association of the Y402H polymorphism in complement factor H gene and neovascular age-related macular degeneration in Chinese patients. Invest Ophthalmol Vis Sci 47: 3242-3246.
99. Levine B, &, Kroemer G, (2008): Autophagy in the pathogenesis of disease. Cell 132: 27-42.
100. Lotery A, &, Trump D, (2007): Progress in defining the molecular biology of age related macular degeneration. Hum Genet 122: 219-236.
101. Lu F, Hu J, Zhao P, et al., (2007): HTRA1 variant increases risk to neovascular age-related macular degeneration in Chinese population. Vision Res 47: 3120-3123.
102. Macular Photocoagulation Study Group (1997): Risk factors for choroidal neovascularization in the second eye of patients with juxtafoveal or subfoveal choroidal neovascularization secondary to age-related macular degeneration. Arch Ophthalmol 115: 741-747.
103. Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, &, Persico M, (1991): Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 88: 9267-9271.
104. Majai G, Petrovski G, &, Fesus L, (2006): Inflammation and the apopto-phagocytic system. Immunol Lett 104: 94-101.
105. Mathew R, Karp CM, Beaudoin B, et al., (2009): Autophagy suppresses tumorigenesis through elimination of p62. Cell 137: 1062-1075.
106. Mimnaugh EG, Xu W, Vos M, Yuan X, Isaacs JS, Bisht KS, Gius D, &, Neckers L, (2004): Simultaneous inhibition of hsp 90 and the proteasome promotes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity. Mol Cancer Ther 3: 551-566.
107. Miyake K, (2007): Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin Immunol 19: 3-10.
108. Mori K, Horie-Inoue K, Kohda M, et al., (2007): Association of the HTRA1 gene variant with age-related macular degeneration in the Japanese population. J Hum Genet 52: 636-641.
109. Nagaoka U, Kim K, Jana NR, Doi H, Maruyama M, Mitsui K, Oyama F, &, Nukina N, (2004): Increased expression of p62 in expanded polyglutamine- expressing cells and its association with polyglutamine inclusions. J Neurochem 91: 57-68.
110. Nandrot EF, Anand M, Almeida D, Atabai K, Sheppard D, &, Finnemann SC, (2007): Essential role for MFG-E8 as ligand for αvβ5 integrin in diurnal retinal phagocytosis. Proc Nat Acad Sci USA 104: 12005-12010.
111. Niederkorn JY, (1990): Immune privilege and immune regulation in the eye. Adv Immunol 48: 191-226.
112. Nordgaard CL, Karunadharma PP, Feng X, Olsen TW, &, Ferrington DA, (2008): Mitochondrial proteomics of the retinal pigment epithelium at progressive stages of age-related macular degeneration. Invest Ophthalmol Vis Sci 49: 2848-2855.
113. Oh H, Takagi H, Takagi C, et al., (1999): The potential angiogenic role of macrophages in the formation of choroidal neovascular membranes. Invest Ophthalmol Vis Sci 40: 1891-1898.
114. Ohno-Matsui K, Yoshida T, Uetama T, Mochizuki M, &, Morita I, (2003): Vascular endothelial growth factor upregulates pigment epithelium-derived factor expression via VEGFR-1 in human retinal pigment epithelial cells. Biochem Biophys Res Commun 303: 962-967.
115. Olofsson B, Pajusola K, Kaipainen A, et al., (1996): Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93: 2576-2581.
116. Oskolkova OV, Afonyushkin T, Leitner A, von Schlieffen E, Gargalovic PS, Lusis AJ, Binder BR, &, Bochkov VN, (2008): ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response. Blood 112: 330-339.
117. Paimela T, Ryhänen T, Mannermaa E, Ojala J, Kalesnykas G, Salminen A, &, Kaarniranta K, (2007): The effect of 17β-estradiol on IL-6 secretion and NF-κB DNA-binding activity in human retinal pigment epithelial cells. Immunol Lett 110: 139-144.
118. Pattingre S, Espert L, Biard-Piechaczyk M, &, Codogno P, (2008): Regulation of macroautophagy by mTOR and Beclin 1 complexes. Biochimie 90: 313-323.
119. Pauleikhoff D, Harper CA, Marshall J, &, Bird AC, (1990): Aging changes in Bruch's membrane. A histochemical and morphologic study. Ophthalmology 97: 171-178.
120. Penfold PL, Killingsworth MC, &, Sarks SH, (1985): Senile macular degeneration: the involvement of immunocompetent cells. Graefes Arch Clin Exp Ophthalmol 223: 69-76.
121. Penfold PL, Provis JM, Furby JH, Gatenby PA, &, Billson FA, (1990): Autoantibodies to retinal astrocytes associated with age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 228: 270-274.
122. Pétrilli V, Dostert C, Muruve DA, &, Tschopp J, (2007): The inflammasome: a danger sensing complex triggering innate immunity. Curr Opin Immunol 19: 615-622.
123. Petrovski G, Berényi E, Moe MC, Vajas A, Fésüs L, Berta A, &, Facskó A, (2011): Clearance of dying ARPE-19 cells by professional & nonprofessional phagocytes in vitro- implications for age-related macular degeneration (AMD). Acta Ophthalmol 89: e30-34.
124. Ramrattan RS, van der Schaft TL, Mooy CM, de Bruijn WC, Mulder PG, &, de Jong PT, (1994): Morphometric analysis of Bruch's membrane, the choriocapillaris, and the choroid in aging. Invest Ophthalmol Vis Sci 35: 2857-2864.
125. Rivera A, Fisher SA, Fritsche LG, Keilhauer CN, Lichtner P, Meitinger T, &, Weber BHF, (2005): Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 14: 3227-3236.
126. Ross RJ, Bojanowski CM, Wang JJ, et al., (2007): The LOC387715 polymorphism and age-related macular degeneration: replication in three case-control samples. Invest Ophthalmol Vis Sci 48: 1128-1132.
127. Ryeom S, Sparrow J, &, Silverstein R, (1996): CD36 participates in the phagocytosis of rod outer segments by retinal pigment epithelium. J Cell Sci 109: 387-395.
128. Ryhanen T, Hyttinen JM, Kopitz J, et al., (2009): Crosstalk between Hsp70 molecular chaperone, lysosomes and proteasomes in autophagy-mediated proteolysis in human retinal pigment epithelial cells. J Cell Mol Med 13: 3616-3631.
129. Ryhanen T, Viiri J, Hyttinen JM, Uusitalo H, Salminen A, &, Kaarniranta K, (2011): Influence of Hsp90 and HDAC inhibition and tubulin acetylation on perinuclear protein aggregation in human retinal pigment epithelial cells. J Biomed Biotechnol 2011: 798052.
130. Saint-Geniez M, Maldonado AE, &, D'Amore PA, (2006): VEGF expression and receptor activation in the choroid during development and in the adult. Invest Ophthalmol Vis Sci 47: 3135-3142.
131. Saint-Geniez M, Maharaj ASR, Walshe TE, et al., (2008): Endogenous VEGF is required for visual function: evidence for a survival role on Muller cells and photoreceptors. PLoS ONE 3: e3554.
132. Salminen A, &, Kaarniranta K, (2009): Regulation of the aging process by autophagy. Trends Mol Med 15: 217-224.
133. Salminen A, Kauppinen A, Hyttinen JM, Toropainen E, &, Kaarniranta K, (2010): Endoplasmic reticulum stress in age-related macular degeneration: trigger for neovascularization. Mol Med 16: 535-542.
134. Sarraf D, Gin T, Yu F, Brannon A, Owens SL, &, Bird AC, (1999): Long-term drusen study. Retina 19: 513-519.
135. Schmid D, &, Münz C, (2007): Innate and adaptive immunity through autophagy. Immunity 27: 11-21.
136. Schmidt S, Klaver C, Saunders A, et al., (2002): A pooled case-control study of the apolipoprotein E (APOE) gene in age-related maculopathy. Ophthalmic Genet 23: 209-223.
137. Seibenhener ML, Babu JR, Geetha T, Wong HC, Krishna NR, &, Wooten MW, (2004): Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol 24: 8055-8068.
138. Seibenhener ML, Geetha T, &, Wooten MW, (2007): Sequestosome 1/p62-more than just a scaffold. FEBS Lett 581: 175-179.
139. Seitsonen S, Lemmela S, Holopainen J, et al., (2006): Analysis of variants in the complement factor H, the elongation of very long chain fatty acids-like 4 and the hemicentin 1 genes of age-related macular degeneration in the Finnish population. Mol Vis 12: 796-801.
140. Seitz HM, Camenisch TD, Lemke G, Earp HS, &, Matsushima GK, (2007): Macrophages and dendritic cells use different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. J Immunol 178: 5635-5642.
141. Senger D, Galli S, Dvorak A, Perruzzi C, Harvey V, &, Dvorak H, (1983): Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219: 983-985.
142. Senger DR, Connolly DT, Van De Water L, Feder J, &, Dvorak HF, (1990): Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res 50: 1774-1778.
143. Seregard S, Algvere PV, &, Berglin L, (1994): Immunohistochemical characterization of surgically removed subfoveal fibrovascular membranes. Graefes Arch Clin Exp Ophthalmol 232: 325-329.
144. Shima DT, Nishijima K, Jo N, &, Adamis AP, (2004): VEGF-mediated neuroprotection in ischemic retina. Invest Ophthalmol Vis Sci 45: 3270.
145. Sivaprasad S, Bailey TA, &, Chong VN, (2005): Bruch's membrane and the vascular intima: is there a common basis for age-related changes and disease?. Clin Experiment Ophthalmol 33: 518-523.
146. Smith W, Assink J, Klein R, et al., (2001): Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology 108: 697-704.
147. Souied EH, Leveziel N, Richard F, Dragon-Durey MA, Coscas G, Soubrane G, Benlian P, &, Fremeaux-Bacchi V, (2005): Y402H complement factor H polymorphism associated with exudative age-related macular degeneration in the French population. Mol Vis 11: 1135-1140.
148. Sparrow JR, &, Boulton M, (2005): RPE lipofuscin and its role in retinal pathobiology. Exp Eye Res 80: 595-606.
149. Sparrow JR, Cai B, Fishkin N, Jang YP, Krane S, Vollmer HR, Zhou J, &, Nakanishi K, (2003): A2E, a fluorophore of RPE lipofuscin: can it cause RPE degeneration? Adv Exp Med Biol 533: 205-211.
150. Stefansson E, Geirsdóttir A, &, Sigurdsson H, (2011): Metabolic physiology in age related macular degeneration. Prog Retin Eye Res 30: 72-80.
151. Strauss O, (2005): The retinal pigment epithelium in visual function. Physiol Rev 85: 845-881.
152. Sundelin S, Wihlmark U, Nilsson SE, &, Brunk UT, (1998): Lipofuscin accumulation in cultured retinal pigment epithelial cells reduces their phagocytic capacity. Curr Eye Res 17: 851-857.
153. Tanimoto S, Tamura H, Ue T, Yamane K, Maruyama H, Kawakami H, &, Kiuchi Y, (2007): A polymorphism of LOC387715 gene is associated with age-related macular degeneration in the Japanese population. Neurosci Lett 414: 71-74.
154. Tate D Jr, Miceli M, &, Newsome D, (1995): Phagocytosis and H2O2 induce catalase and metallothionein gene expression in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 36: 1271-1279.
155. Terman A, &, Brunk UT, (2004): Lipofuscin. Int J Biochem Cell Biol 36: 1400-1404.
156. Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, &, Böhlen P, (1992): Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 187: 1579-1586.
157. Valamanesh F, Torriglia A, Savoldelli M, Gandolphe C, Jeanny JC, BenEzra D, &, Behar-Cohen F, (2007): Glucocorticoids induce retinal toxicity through mechanisms mainly associated with paraptosis. Mol Vis 13: 1746-1757.
158. Viiri J, Hyttinen JM, Ryhanen T, et al., (2010): P62/sequestosome 1 as a regulator of proteasome inhibitor-induced autophagy in human retinal pigment epithelial cells. Mol Vis 16: 1399-1414.
159. Wang AL, Lukas TJ, Yuan M, Du N, Tso MO, &, Neufeld AH, (2009): Autophagy, exosomes and drusen formation in age-related macular degeneration. Autophagy 5: 563-564.
160. Warburton S, Southwick K, Hardman RM, et al., (2005): Examining the proteins of functional retinal lipofuscin using proteomic analysis as a guide for understanding its origin. Mol Vis 11: 1122-1134.
161. Wassell J, Davies S, Bardsley W, &, Boulton M, (1999): The photoreactivity of the retinal age pigment lipofuscin. J Biol Chem 274: 23828-23832.
162. Weger M, Renner W, Steinbrugger I, et al., (2007): Association of the HTRA1 -625G>A promoter gene polymorphism with exudative age-related macular degeneration in a Central European population. Mol Vis 13: 1274-1279.
163. Wing G, Blanchard G, &, Weiter J, (1978): The topography and age relationship of lipofuscin concentration in the retinal pigment epithelium. Invest Ophthalmol Vis Sci 17: 601-607.
164. Winkler BS, Boulton ME, Gottsch JD, &, Sternberg P, (1999): Oxidative damage and age-related macular degeneration. Mol Vis 5: 32.
165. Wojcik C, (2002): Regulation of apoptosis by the ubiquitin and proteasome pathway. J Cell Mol Med 6: 25-48.
166. Xie Z, &, Klionsky DJ, (2007): Autophagosome formation: core machinery and adaptations. Nat Cell Biol 9: 1102-1109.
167. Xu H, Dawson R, Forrester JV, &, Liversidge J, (2007): Identification of novel dendritic cell populations in normal mouse retina. Invest Ophthalmol Vis Sci 48: 1701-1710.
168. Yamada Y, Ishibashi K, Ishibashi K, Bhutto IA, Tian J, Lutty GA, &, Handa JT, (2006): The expression of advanced glycation endproduct receptors in rpe cells associated with basal deposits in human maculas. Exp Eye Res 82: 840-848.
169. Yang Z, Camp NJ, Sun H, et al., (2006): A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314: 992-993.
170. Yang D, Elner SG, Bian Z, Till GO, Petty HR, &, Elner VM, (2007): Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells. Exp Eye Res 85: 462-472.
171. Yi X, Mai L, Uyama M, &, Yew DTW, (1998): Time-course expression of vascular endothelial growth factor as related to the development of the retinochoroidal vasculature in rats. Exp Brain Res 118: 155-160.
172. Yorimitsu T, &, Klionsky DJ, (2005): Autophagy: molecular machinery for self-eating. Cell Death Differ 12 (Suppl 2): 1542-1552.
173. Yorimitsu T, Nair U, Yang Z, &, Klionsky DJ, (2006): Endoplasmic reticulum stress triggers autophagy. J Biol Chem 281: 30299-30304.
174. Yoshida T, DeWan A, Zhang H, et al., (2007): HTRA1 promoter polymorphism predisposes Japanese to age-related macular degeneration. Mol Vis 13: 545-548.
175. Zareparsi S, Reddick AC, Branham KE, et al., (2004): Association of apolipoprotein E alleles with susceptibility to age-related macular degeneration in a large cohort from a single center. Invest Ophthalmol Vis Sci 45: 1306-1310.
176. Zatloukal K, Stumptner C, Fuchsbichler A, et al., (2002): p62 is a common component of cytoplasmic inclusions in protein aggregation diseases. Am J Pathol 160: 255-263.