Parainflammation, chronic inflammation, and age-related macular degeneration

Journal of Leukocyte Biology

Volumn 98, Issue 5, 2015, Pages 713-725

  Chen, Mei ^a   Xu, Heping ^a  

^a QUEEN'S UNIVERSITY BELFAST   (United Kingdom)

Author keywords

Blood retina barrier; Complement; Immune privilege; Microglia; Retina

Indexed keywords

ADAPTIVE IMMUNITY; AGE RELATED MACULAR DEGENERATION; AGING; CHRONIC INFLAMMATION; HUMAN; IMMUNE DYSREGULATION; IMMUNE SYSTEM; INNATE IMMUNITY; NONHUMAN; OXIDATIVE STRESS; PARAINFLAMMATION; PIGMENT EPITHELIUM; PRIORITY JOURNAL; RETINA; REVIEW; ANIMAL; CHRONIC DISEASE; GENETIC PREDISPOSITION; GENETICS; IMMUNOLOGY; INFLAMMATION; MACULAR DEGENERATION; MICROGLIA; PATHOLOGY;

AGING; ANIMALS; CHRONIC DISEASE; GENETIC PREDISPOSITION TO DISEASE; HUMANS; IMMUNITY, INNATE; INFLAMMATION; MACULAR DEGENERATION; MICROGLIA;

EID: 84944103518     PISSN: 07415400     EISSN: 19383673     Source Type: Journal    
DOI: 10.1189/jlb.3RI0615-239R     Document Type: Review

References (180)

1. Mangge, H., Almer, G., Truschnig-Wilders, M., Schmidt, A., Gasser, R., Fuchs, D. (2010) Inflammation, adiponectin, obesity and cardiovascular risk. Curr. Med. Chem. 17, 4511-4520.
2. Mathieu, P., Lemieux, I., Després, J. P. (2010) Obesity, inflammation, and cardiovascular risk. Clin. Pharmacol. Ther. 87, 407-416.
3. Lathe, R., Sapronova, A., Kotelevtsev, Y. (2014) Atherosclerosis and Alzheimer-diseases with a common cause? Inflammation, oxysterols, vasculature. BMC Geriatr. 14, 36.
4. Stoll, G., Bendszus, M. (2006) Inflammation and atherosclerosis: novel insights into plaque formation and destabilization. Stroke 37, 1923-1932.
5. McGeer, P. L., McGeer, E. G. (2004) Inflammation and the degenerative diseases of aging. Ann. N. Y. Acad. Sci. 1035, 104-116.
6. Cameron, B., Landreth, G. E. (2010) Inflammation, microglia, and Alzheimer's disease. Neurobiol. Dis. 37, 503-509.
7. McGeer, P. L., McGeer, E. G. (2004) Inflammation and neurodegeneration in Parkinson's disease. Parkinsonism Relat. Disord. 10 (Suppl 1), S3-S7.
8. Whitton, P. S. (2007) Inflammation as a causative factor in the aetiology of Parkinson's disease. Br. J. Pharmacol. 150, 963-976.
9. Anderson, D. H., Mullins, R. F., Hageman, G. S., Johnson, L. V. (2002) A role for local inflammation in the formation of drusen in the aging eye. Am. J. Ophthalmol. 134, 411-431.
10. Ambati, J., Atkinson, J. P., Gelfand, B. D. (2013) Immunology of agerelated macular degeneration. Nat. Rev. Immunol. 13, 438-451.
11. Medzhitov, R. (2008) Origin and physiological roles of inflammation. Nature 454, 428-435.
12. Goto, M. (2008) Inflammaging (inflammation + aging): a driving force for human aging based on an evolutionarily antagonistic pleiotropy theory? Biosci. Trends 2, 218-230.
13. Franceschi, C., Campisi, J. (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci. 69 (Suppl 1), S4-S9.
14. Wong, W. L., Su, X., Li, X., Cheung, C. M., Klein, R., Cheng, C. Y., Wong, T. Y. (2014) Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health 2, e106-e116.
15. Coleman, H. R., Chan, C. C., Ferris III, F. L., Chew, E. Y. (2008) Agerelated macular degeneration. Lancet 372, 1835-1845.
16. Jager, R. D., Mieler, W. F., Miller, J. W. (2008) Age-related macular degeneration. N. Engl. J. Med. 358, 2606-2617.
17. Ramrattan, R. S., van der Schaft, T. L., Mooy, C. M., de Bruijn, W. C., Mulder, P. G., de Jong, P. T. (1994) Morphometric analysis of Bruch's membrane, the choriocapillaris, and the choroid in aging. Invest. Ophthalmol. Vis. Sci. 35, 2857-2864.
18. Hjelmeland, L. M., Cristofolo, V. J., Funk, W., Rakoczy, E., Katz, M. L. (1999) Senescence of the retinal pigment epithelium. Mol. Vis. 5, 33.
19. Boulton, M., Dayhaw-Barker, P. (2001) The role of the retinal pigment epithelium: topographical variation and ageing changes. Eye (Lond.) 15, 384-389.
20. Hageman, G. S., Luthert, P. J., Victor Chong, N. H., Johnson, L. V., Anderson, D. H., Mullins, R. F. (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.
21. VanNewkirk, M. R., Nanjan, M. B., Wang, J. J., Mitchell, P., Taylor, H. R., McCarty, C. A. (2000) The prevalence of age-related maculopathy: the visual impairment project. Ophthalmology 107, 1593-1600.
22. Joachim, N., Mitchell, P., Rochtchina, E., Tan, A. G., Wang, J. J. (2014) Incidence and progression of reticular drusen in age-related macular degeneration: findings from an older Australian cohort. Ophthalmology 121, 917-925.
23. Chakravarthy, U., Harding, S. P., Rogers, C. A., Downes, S. M., Lotery, A. J., Wordsworth, S., Reeves, B. C.; IVAN Study Investigators. (2012) Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology 119, 1399-1411.
24. Martin, D. F., Maguire, M. G., Fine, S. L., Ying, G. S., Jaffe, G. J., Grunwald, J. E., Toth, C., Redford, M., Ferris III, F. L.; Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. (2012) Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 119, 1388-1398.
25. Rofagha, S., Bhisitkul, R. B., Boyer, D. S., Sadda, S. R., Zhang, K.; SEVEN-UP Study Group. (2013) Seven-year outcomes in ranibizumabtreated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology 120, 2292-2299.
26. Ding, X., Patel, M., Chan, C. C. (2009) Molecular pathology of agerelated macular degeneration. Prog. Retin. Eye Res. 28, 1-18.
27. Anderson, D. H., Radeke, M. J., Gallo, N. B., Chapin, E. A., Johnson, P. T., Curletti, C. R., Hancox, L. S., Hu, J., Ebright, J. N., Malek, G., Hauser, M. A., Rickman, C. B., Bok, D., Hageman, G. S., Johnson, L. V. (2010) The pivotal role of the complement system in aging and agerelated macular degeneration: hypothesis re-visited. Prog. Retin. Eye Res. 29, 95-112.
28. Penfold, P. L., Killingsworth, M. C., Sarks, S. H. (1985) Senile macular degeneration: the involvement of immunocompetent cells. Graefes Arch. Clin. Exp. Ophthalmol. 223, 69-76.
29. Penfold, P. L., Liew, S. C., Madigan, M. C., Provis, J. M. (1997) Modulation of major histocompatibility complex class II expression in retinas with age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 38, 2125-2133.
30. Tuo, J., Grob, S., Zhang, K., Chan, C. C. (2012) Genetics of immunological and inflammatory components in age-related macular degeneration. Ocul. Immunol. Inflamm. 20, 27-36.
31. Ambati, J., Anand, A., Fernandez, S., Sakurai, E., Lynn, B. C., Kuziel, W. A., Rollins, B. J., Ambati, B. K. (2003) An animal model of agerelated macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Nat. Med. 9, 1390-1397.
32. Combadière, C., Feumi, C., Raoul, W., Keller, N., Rodéro, M., Pézard, A., Lavalette, S., Houssier, M., Jonet, L., Picard, E., Debré, P., Sirinyan, M., Deterre, P., Ferroukhi, T., Cohen, S. Y., Chauvaud, D., Jeanny, J. C., Chemtob, S., Behar-Cohen, F., Sennlaub, F. (2007) CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J. Clin. Invest. 117, 2920-2928.
33. Chen, M., Hombrebueno, J. R., Luo, C., Penalva, R., Zhao, J., Colhoun, L., Pandi, S. P., Forrester, J. V., Xu, H. (2013) Age- and light-dependent development of localised retinal atrophy in CCL2(2/2)CX3CR1(GFP/ GFP) mice. PLoS One 8, e61381.
34. Chen, M., Forrester, J. V., Xu, H. (2011) Dysregulation in retinal parainflammation and age-related retinal degeneration in CCL2 or CCR2 deficient mice. PLoS One 6, e22818.
35. Ufret-Vincenty, R. L., Aredo, B., Liu, X., McMahon, A., Chen, P. W., Sun, H., Niederkorn, J. Y., Kedzierski, W. (2010) Transgenic mice expressing variants of complement factor H develop AMD-like retinal findings. Invest. Ophthalmol. Vis. Sci. 51, 5878-5887.
36. Medzhitov, R. (2010) Inflammation 2010: new adventures of an old flame. Cell 140, 771-776.
37. Johnson, J. D., Fleshner, M. (2006) Releasing signals, secretory pathways, and immune function of endogenous extracellular heat shock protein 72. J. Leukoc. Biol. 79, 425-434.
38. Yenari, M. A., Giffard, R. G., Sapolsky, R. M., Steinberg, G. K. (1999) The neuroprotective potential of heat shock protein 70 (HSP70). Mol. Med. Today 5, 525-531.
39. Burel, C., Mezger, V., Pinto, M., Rallu, M., Trigon, S., Morange, M. (1992) Mammalian heat shock protein families. Expression and functions. Experientia 48, 629-634.
40. Navarro-Yepes, J., Burns, M., Anandhan, A., Khalimonchuk, O., del Razo, L. M., Quintanilla-Vega, B., Pappa, A., Panayiotidis, M. I., Franco, R. (2014) Oxidative stress, redox signaling, and autophagy: cell death versus survival. Antioxid. Redox Signal. 21, 66-85.
41. Blasiak, J., Petrovski, G., Veréb, Z., Facskó, A., Kaarniranta, K. (2014) Oxidative stress, hypoxia, and autophagy in the neovascular processes of age-related macular degeneration. BioMed Res. Int. 2014, 768026.
42. Levine, B., Mizushima, N., Virgin, H. W. (2011) Autophagy in immunity and inflammation. Nature 469, 323-335.
43. Cuervo, A. M., Bergamini, E., Brunk, U. T., Dröge, W., Ffrench, M., Terman, A. (2005) Autophagy and aging: the importance of maintaining "clean" cells. Autophagy 1, 131-140.
44. Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J., Kirkland, J. L. (2013) Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966-972.
45. Sasaki, M., Miyakoshi, M., Sato, Y., Nakanuma, Y. (2010) Modulation of the microenvironment by senescent biliary epithelial cells may be involved in the pathogenesis of primary biliary cirrhosis. J. Hepatol. 53, 318-325.
46. Severino, V., Alessio, N., Farina, A., Sandomenico, A., Cipollaro, M., Peluso, G., Galderisi, U., Chambery, A. (2013) Insulin-like growth factor binding proteins 4 and 7 released by senescent cells promote premature senescence in mesenchymal stem cells. Cell Death Dis. 4, e911.
47. Davalos, A. R., Coppe, J. P., Campisi, J., Desprez, P. Y. (2010) Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev. 29, 273-283.
48. Fumagalli, M., d'Adda di Fagagna, F. (2009) SASPense and DDRama in cancer and ageing. Nat. Cell Biol. 11, 921-923.
49. Ghaemi-Oskouie, F., Shi, Y. (2011) The role of uric acid as an endogenous danger signal in immunity and inflammation. Curr. Rheumatol. Rep. 13, 160-166.
50. Park, J. S., Gamboni-Robertson, F., He, Q., Svetkauskaite, D., Kim, J. Y., Strassheim, D., Sohn, J. W., Yamada, S., Maruyama, I., Banerjee, A., Ishizaka, A., Abraham, E. (2006) High mobility group box 1 protein interacts with multiple Toll-like receptors. Am. J. Physiol. Cell Physiol. 290, C917-C924.
51. Bianchi, M. E., Manfredi, A. A. (2007) High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol. Rev. 220, 35-46.
52. Dumitriu, I. E., Baruah, P., Manfredi, A. A., Bianchi, M. E., Rovere- Querini, P. (2005) HMGB1: guiding immunity from within. Trends Immunol. 26, 381-387.
53. Sen, J., Belli, A. (2007) S100B in neuropathologic states: the CRP of the brain? J. Neurosci. Res. 85, 1373-1380.
54. Matzinger, P. (2002) The danger model: a renewed sense of self. Science 296, 301-305.
55. Streilein, J. W., Ma, N., Wenkel, H., Ng, T. F., Zamiri, P. (2002) Immunobiology and privilege of neuronal retina and pigment epithelium transplants. Vision Res. 42, 487-495.
56. Forrester, J. V., Xu, H., Lambe, T., Cornall, R. (2008) Immune privilege or privileged immunity? Mucosal Immunol. 1, 372-381.
57. Gregerson, D. S. (1998) Immune privilege in the retina. Ocul. Immunol. Inflamm. 6, 257-267.
58. Forrester, J. V., Xu, H. (2012) Good news-bad news: the Yin and Yang of immune privilege in the eye. Front. Immunol. 3, 338.
59. Avichezer, D., Grajewski, R. S., Chan, C. C., Mattapallil, M. J., Silver, P. B., Raber, J. A., Liou, G. I., Wiggert, B., Lewis, G. M., Donoso, L. A., Caspi, R. R. (2003) An immunologically privileged retinal antigen elicits tolerance: major role for central selection mechanisms. J. Exp. Med. 198, 1665-1676.
60. Forrester, J. V., Xu, H., Kuffová, L., Dick, A. D., McMenamin, P. G. (2010) Dendritic cell physiology and function in the eye. Immunol. Rev. 234, 282-304.
61. Streilein, J. W. (1999) Immunoregulatory mechanisms of the eye. Prog. Retin. Eye Res. 18, 357-370.
62. Wenkel, H., Streilein, J. W. (2000) Evidence that retinal pigment epithelium functions as an immune-privileged tissue. Invest. Ophthalmol. Vis. Sci. 41, 3467-3473.
63. Dick, A. D., Carter, D., Robertson, M., Broderick, C., Hughes, E., Forrester, J. V., Liversidge, J. (2003) Control of myeloid activity during retinal inflammation. J. Leukoc. Biol. 74, 161-166.
64. Mochizuki, M., Sugita, S., Kamoi, K. (2013) Immunological homeostasis of the eye. Prog. Retin. Eye Res. 33, 10-27.
65. Kawazoe, Y., Sugita, S., Keino, H., Yamada, Y., Imai, A., Horie, S., Mochizuki, M. (2012) Retinoic acid from retinal pigment epithelium induces T regulatory cells. Exp. Eye Res. 94, 32-40.
66. Horie, S., Sugita, S., Futagami, Y., Yamada, Y., Mochizuki, M. (2010) Human retinal pigment epithelium-induced CD4+CD25+ regulatory T cells suppress activation of intraocular effector T cells. Clin. Immunol. 136, 83-95.
67. Sugita, S., Usui, Y., Horie, S., Futagami, Y., Aburatani, H., Okazaki, T., Honjo, T., Takeuchi, M., Mochizuki, M. (2009) T-cell suppression by programmed cell death 1 ligand 1 on retinal pigment epithelium during inflammatory conditions. Invest. Ophthalmol. Vis. Sci. 50, 2862-2870.
68. Sugita, S., Horie, S., Nakamura, O., Futagami, Y., Takase, H., Keino, H., Aburatani, H., Katunuma, N., Ishidoh, K., Yamamoto, Y., Mochizuki, M. (2008) Retinal pigment epithelium-derived CTLA-2alpha induces TGFbeta-producing T regulatory cells. J. Immunol. 181, 7525-7536.
69. Zamiri, P., Masli, S., Kitaichi, N., Taylor, A. W., Streilein, J. W. (2005) Thrombospondin plays a vital role in the immune privilege of the eye. Invest. Ophthalmol. Vis. Sci. 46, 908-919.
70. Ferguson, T. A., Griffith, T. S. (1997) A vision of cell death: insights into immune privilege. Immunol. Rev. 156, 167-184.
71. Kazama, H., Ricci, J. E., Herndon, J. M., Hoppe, G., Green, D. R., Ferguson, T. A. (2008) Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity 29, 21-32.
72. Ferguson, T. A., Griffith, T. S. (2007) The role of Fas ligand and TNFrelated apoptosis-inducing ligand (TRAIL) in the ocular immune response. Chem. Immunol. Allergy 92, 140-154.
73. Sohn, J. H., Kaplan, H. J., Suk, H. J., Bora, P. S., Bora, N. S. (2000) Chronic low level complement activation within the eye is controlled by intraocular complement regulatory proteins. Invest. Ophthalmol. Vis. Sci. 41, 3492-3502.
74. Sohn, J. H., Bora, P. S., Jha, P., Tezel, T. H., Kaplan, H. J., Bora, N. S. (2007) Complement, innate immunity and ocular disease. Chem. Immunol. Allergy 92, 105-114.
75. Taylor, A. W. (1996) Neuroimmunomodulation in immune privilege: role of neuropeptides in ocular immunosuppression. Neuroimmunomodulation 3, 195-204.
76. Taylor, A. W., Lee, D. (2010) Applications of the role of a-MSH in ocular immune privilege. Adv. Exp. Med. Biol. 681, 143-149.
77. Li, L., Eter, N., Heiduschka, P. (2015) The microglia in healthy and diseased retina. Exp. Eye Res. 136, 116-130.
78. Karlstetter, M., Scholz, R., Rutar, M., Wong, W. T., Provis, J. M., Langmann, T. (2015) Retinal microglia: just bystander or target for therapy? Prog. Retin. Eye Res. 45, 30-57.
79. Karlstetter, M., Ebert, S., Langmann, T. (2010) Microglia in the healthy and degenerating retina: insights from novel mouse models. Immunobiology 215, 685-691.
80. Langmann, T. (2007) Microglia activation in retinal degeneration. J. Leukoc. Biol. 81, 1345-1351.
81. Lehnardt, S., Henneke, P., Lien, E., Kasper, D. L., Volpe, J. J., Bechmann, I., Nitsch, R., Weber, J. R., Golenbock, D. T., Vartanian, T. (2006) A mechanism for neurodegeneration induced by group B streptococci through activation of the TLR2/MyD88 pathway in microglia. J. Immunol. 177, 583-592.
82. Jack, C. S., Arbour, N., Manusow, J., Montgrain, V., Blain, M., McCrea, E., Shapiro, A., Antel, J. P. (2005) TLR signaling tailors innate immune responses in human microglia and astrocytes. J. Immunol. 175, 4320-4330.
83. Dick, A. D., Ford, A. L., Forrester, J. V., Sedgwick, J. D. (1995) Flow cytometric identification of a minority population of MHC class II positive cells in the normal rat retina distinct from CD45lowCD11b/c +CD4low parenchymal microglia. Br. J. Ophthalmol. 79, 834-840.
84. Fischer, H. G., Reichmann, G. (2001) Brain dendritic cells and macrophages/microglia in central nervous system inflammation. J. Immunol. 166, 2717-2726.
85. Tavazzi, E., Morrison, D., Sullivan, P., Morgello, S., Fischer, T. (2014) Brain inflammation is a common feature of HIV-infected patients without HIV encephalitis or productive brain infection. Curr. HIV Res. 12, 97-110.
86. Soulas, C., Donahue, R. E., Dunbar, C. E., Persons, D. A., Alvarez, X., Williams, K. C. (2009) Genetically modified CD34+ hematopoietic stem cells contribute to turnover of brain perivascular macrophages in longterm repopulated primates. Am. J. Pathol. 174, 1808-1817.
87. Zhang, J., Wu, G. S., Ishimoto, S., Pararajasegaram, G., Rao, N. A. (1997) Expression of major histocompatibility complex molecules in rodent retina. Immunohistochemical study. Invest. Ophthalmol. Vis. Sci. 38, 1848-1857.
88. Gregerson, D. S., Yang, J. (2003) CD45-positive cells of the retina and their responsiveness to in vivo and in vitro treatment with IFN-gamma or anti-CD40. Invest. Ophthalmol. Vis. Sci. 44, 3083-3093.
89. Lehmann, U., Heuss, N. D., McPherson, S. W., Roehrich, H., Gregerson, D. S. (2010) Dendritic cells are early responders to retinal injury. Neurobiol. Dis. 40, 177-184.
90. Chen, X., Kezic, J., Bernard, C., McMenamin, P. G. (2013) Rd8 mutation in the Crb1 gene of CD11c-eYFP transgenic reporter mice results in abnormal numbers of CD11c-positive cells in the retina. J. Neuropathol. Exp. Neurol. 72, 782-790.
91. Xu, H., Dawson, R., Forrester, J. V., Liversidge, J. (2007) Identification of novel dendritic cell populations in normal mouse retina. Invest. Ophthalmol. Vis. Sci. 48, 1701-1710.
92. Zipfel, P. F., Skerka, C. (2009) Complement regulators and inhibitory proteins. Nat. Rev. Immunol. 9, 729-740.
93. Chen, M., Muckersie, E., Luo, C., Forrester, J. V., Xu, H. (2010) Inhibition of the alternative pathway of complement activation reduces inflammation in experimental autoimmune uveoretinitis. Eur. J. Immunol. 40, 2870-2881.
94. Copland, D. A., Hussain, K., Baalasubramanian, S., Hughes, T. R., Morgan, B. P., Xu, H., Dick, A. D., Nicholson, L. B. (2010) Systemic and local anti-C5 therapy reduces the disease severity in experimental autoimmune uveoretinitis. Clin. Exp. Immunol. 159, 303-314.
95. Vergani, S., Di Mauro, E., Davies, E. T., Spinelli, D., Mieli-Vergani, G., Vergani, D. (1986) Complement activation in uveitis. Br. J. Ophthalmol. 70, 60-63.
96. Yang, Y., Lu, H. L., Zhang, J., Yu, H. Y., Wang, H. W., Zhang, M. X., Cianflone, K. (2006) Relationships among acylation stimulating protein, adiponectin and complement C3 in lean vs obese type 2 diabetes. Int. J. Obes. 30, 439-446.
97. Luo, C., Chen, M., Xu, H. (2011) Complement gene expression and regulation in mouse retina and retinal pigment epithelium/choroid. Mol. Vis. 17, 1588-1597.
98. Chen, M., Forrester, J. V., Xu, H. (2007) Synthesis of complement factor H by retinal pigment epithelial cells is down-regulated by oxidized photoreceptor outer segments. Exp. Eye Res. 84, 635-645.
99. Chen, M., Muckersie, E., Robertson, M., Forrester, J. V., Xu, H. (2008) Up-regulation of complement factor B in retinal pigment epithelial cells is accompanied by complement activation in the aged retina. Exp. Eye Res. 87, 543-550.
100. Xu, H., Chen, M., Forrester, J. V. (2009) Para-inflammation in the aging retina. Prog. Retin. Eye Res. 28, 348-368.
101. Glenn, J. V., Mahaffy, H., Wu, K., Smith, G., Nagai, R., Simpson, D. A., Boulton, M. E., Stitt, A. W. (2009) Advanced glycation end product (AGE) accumulation on Bruch's membrane: links to age-related RPE dysfunction. Invest. Ophthalmol. Vis. Sci. 50, 441-451.
102. Ramasamy, R., Vannucci, S. J., Yan, S. S., Herold, K., Yan, S. F., Schmidt, A. M. (2005) Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology 15, 16R-28R.
103. Tian, J., Ishibashi, K., Ishibashi, K., Reiser, K., Grebe, R., Biswal, S., Gehlbach, P., Handa, J. T. (2005) Advanced glycation endproductinduced aging of the retinal pigment epithelium and choroid: a comprehensive transcriptional response. Proc. Natl. Acad. Sci. USA 102, 11846-11851.
104. Mullins, R. F., Russell, S. R., Anderson, D. H., Hageman, G. S. (2000) Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J. 14, 835-846.
105. Johnson, L. V., Leitner, W. P., Rivest, A. J., Staples, M. K., Radeke, M. J., Anderson, D. H. (2002) The Alzheimer's A beta -peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc. Natl. Acad. Sci. USA 99, 11830-11835.
106. Sparrow, J. R., Fishkin, N., Zhou, J., Cai, B., Jang, Y. P., Krane, S., Itagaki, Y., Nakanishi, K. (2003) A2E, a byproduct of the visual cycle. Vision Res. 43, 2983-2990.
107. Inoue, Y., Yoneda, M., Miyaishi, O., Iwaki, M., Zako, M. (2009) Hyaluronan dynamics during retinal development. Brain Res. 1256, 55-60.
108. Steinle, J. J., Sharma, S., Smith, C. P.,McFayden-Ketchum, L. S. (2009) Normal aging involves modulation of specific inflammatory markers in the rat retina and choroid. J. Gerontol. A Biol. Sci. Med. Sci. 64, 325-331.
109. Chen, M., Muckersie, E., Forrester, J. V., Xu, H. (2010) Immune activation in retinal aging: a gene expression study. Invest. Ophthalmol. Vis. Sci. 51, 5888-5896.
110. Ida, H., Boylan, S. A., Weigel, A. L., Hjelmeland, L. M. (2003) Agerelated changes in the transcriptional profile of mouse RPE/choroid. Physiol. Genomics 15, 258-262.
111. Chen, H., Liu, B., Lukas, T. J., Neufeld, A. H. (2008) The aged retinal pigment epithelium/choroid: a potential substratum for the pathogenesis of age-related macular degeneration. PLoS One 3, e2339.
112. Kurji, K. H., Cui, J. Z., Lin, T., Harriman, D., Prasad, S. S., Kojic, L., Matsubara, J. A. (2010) Microarray analysis identifies changes in inflammatory gene expression in response to amyloid-beta stimulation of cultured human retinal pigment epithelial cells. Invest. Ophthalmol. Vis. Sci. 51, 1151-1163.
113. Liu, C., Cao, L., Yang, S., Xu, L., Liu, P., Wang, F., Xu, D. (2015) Subretinal injection of amyloid-b peptide accelerates RPE cell senescence and retinal degeneration. Int. J. Mol. Med. 35, 169-176.
114. Liu, X. C., Liu, X. F., Jian, C. X., Li, C. J., He, S. Z. (2012) IL-33 is induced by amyloid-b stimulation and regulates inflammatory cytokine production in retinal pigment epithelium cells. Inflammation 35, 776-784.
115. Chan-Ling, T., Hughes, S., Baxter, L., Rosinova, E., McGregor, I., Morcos, Y., van Nieuwenhuyzen, P., Hu, P. (2007) Inflammation and breakdown of the blood-retinal barrier during "physiological aging" in the rat retina: a model for CNS aging. Microcirculation 14, 63-76.
116. Xu, H., Chen, M., Manivannan, A., Lois, N., Forrester, J. V. (2008) Agedependent accumulation of lipofuscin in perivascular and subretinal microglia in experimental mice. Aging Cell 7, 58-68.
117. Ardeljan, D., Chan, C. C. (2013) Aging is not a disease: distinguishing age-related macular degeneration from aging. Prog. Retin. Eye Res. 37, 68-89.
118. Aspengren, S., Hedberg, D., Wallin, M. (2006) Studies of pigment transfer between Xenopus laevis melanophores and fibroblasts in vitro and in vivo. Pigment Cell Res. 19, 136-145.
119. Luo, C., Zhao, J., Madden, A., Chen, M., Xu, H. (2013) Complement expression in retinal pigment epithelial cells is modulated by activated macrophages. Exp. Eye Res. 112, 93-101.
120. Seth, A., Cui, J., To, E., Kwee, M., Matsubara, J. (2008) Complementassociated deposits in the human retina. Invest. Ophthalmol. Vis. Sci. 49, 743-750.
121. Zhao, T., Gao, J., Van, J., To, E., Wang, A., Cao, S., Cui, J. Z., Guo, J. P., Lee, M., McGeer, P. L., Matsubara, J. A. (2015) Age-related increases in amyloid beta and membrane attack complex: evidence of inflammasome activation in the rodent eye. J. Neuroinflammation 12, 121.
122. Rus, H. G., Niculescu, F., Shin, M. L. (1996) Sublytic complement attack induces cell cycle in oligodendrocytes. J. Immunol. 156, 4892-4900.
123. Tegla, C. A., Cudrici, C., Rus, V., Ito, T., Vlaicu, S., Singh, A., Rus, H. (2009) Neuroprotective effects of the complement terminal pathway during demyelination: implications for oligodendrocyte survival. J. Neuroimmunol. 213, 3-11.
124. Tarallo, V., Hirano, Y., Gelfand, B. D., Dridi, S., Kerur, N., Kim, Y., Cho, W. G., Kaneko, H., Fowler, B. J., Bogdanovich, S., Albuquerque, R. J., Hauswirth, W. W., Chiodo, V. A., Kugel, J. F., Goodrich, J. A., Ponicsan, S. L., Chaudhuri, G., Murphy, M. P., Dunaief, J. L., Ambati, B. K., Ogura, Y., Yoo, J. W., Lee, D. K., Provost, P., Hinton, D. R., Núñez, G., Baffi, J. Z., Kleinman, M. E., Ambati, J. (2012) DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell 149, 847-859.
125. Tseng, W. A., Thein, T., Kinnunen, K., Lashkari, K., Gregory, M. S., D'Amore, P. A., Ksander, B. R. (2013) NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 54, 110-120.
126. Liu, R. T., Gao, J., Cao, S., Sandhu, N., Cui, J. Z., Chou, C. L., Fang, E., Matsubara, J. A. (2013) Inflammatory mediators induced by amyloidbeta in the retina and RPE in vivo: implications for inflammasome activation in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 54, 2225-2237.
127. Anderson, O. A., Finkelstein, A., Shima, D. T. (2013) A2E induces IL-1ß production in retinal pigment epithelial cells via the NLRP3 inflammasome. PLoS One 8, e67263.
128. Brandstetter, C., Mohr, L. K., Latz, E., Holz, F. G., Krohne, T. U. (2015) Light induces NLRP3 inflammasome activation in retinal pigment epithelial cells via lipofuscin-mediated photooxidative damage. J. Mol. Med. (Berl). 93, 905-916.
129. Kauppinen, A., Niskanen, H., Suuronen, T., Kinnunen, K., Salminen, A., Kaarniranta, K. (2012) Oxidative stress activates NLRP3 inflammasomes in ARPE-19 cells-implications for age-related macular degeneration (AMD). Immunol. Lett. 147, 29-33.
130. Kerur, N., Hirano, Y., Tarallo, V., Fowler, B. J., Bastos-Carvalho, A., Yasuma, T., Yasuma, R., Kim, Y., Hinton, D. R., Kirschning, C. J., Gelfand, B. D., Ambati, J. (2013) TLR-independent and P2X7- dependent signaling mediate Alu RNA-induced NLRP3 inflammasome activation in geographic atrophy. Invest. Ophthalmol. Vis. Sci. 54, 7395-7401.
131. Sparrow, J. R., Cai, B., Fishkin, N., Jang, Y. P., Krane, S., Vollmer, H. R., Zhou, J., Nakanishi, K. (2003) A2E, a fluorophore of RPE lipofuscin: can it cause RPE degeneration? Adv. Exp. Med. Biol. 533, 205-211.
132. Wang, A. L., Lukas, T. J., Yuan, M., Du, N., Tso, M. O., Neufeld, A. H. (2009) Autophagy and exosomes in the aged retinal pigment epithelium: possible relevance to drusen formation and age-related macular degeneration. PLoS One 4, e4160.
133. Mitter, S. K., Song, C., Qi, X., Mao, H., Rao, H., Akin, D., Lewin, A., Grant, M., Dunn, Jr., W., Ding, J., Bowes Rickman, C., Boulton, M. (2014) Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Autophagy 10, 1989-2005.
134. Viiri, J., Amadio, M., Marchesi, N., Hyttinen, J. M., Kivinen, N., Sironen, R., Rilla, K., Akhtar, S., Provenzani, A., D'Agostino, V. G., Govoni, S., Pascale, A., Agostini, H., Petrovski, G., Salminen, A., Kaarniranta, K. (2013) Autophagy activation clears ELAVL1/HuR-mediated accumulation of SQSTM1/p62 during proteasomal inhibition in human retinal pigment epithelial cells. PLoS One 8, e69563.
135. Valapala, M., Wilson, C., Hose, S., Bhutto, I. A., Grebe, R., Dong, A., Greenbaum, S., Gu, L., Sengupta, S., Cano, M., Hackett, S., Xu, G., Lutty, G. A., Dong, L., Sergeev, Y., Handa, J. T., Campochiaro, P., Wawrousek, E., Zigler, Jr., J. S., Sinha, D. (2014) Lysosomal-mediated waste clearance in retinal pigment epithelial cells is regulated by CRYBA1/bA3/A1-crystallin via V-ATPase-MTORC1 signaling. Autophagy 10, 480-496.
136. Zhao, H., Roychoudhury, J., Doggett, T. A., Apte, R. S., Ferguson, T. A. (2013) Age-dependent changes in FasL (CD95L) modulate macrophage function in a model of age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 54, 5321-5331.
137. Bhutto, I. A., Baba, T., Merges, C., Juriasinghani, V., McLeod, D. S., Lutty, G. A. (2011) C-Reactive protein and complement factor H in aged human eyes and eyes with age-related macular degeneration. Br. J. Ophthalmol. 95, 1323-1330.
138. Ebrahimi, K. B., Fijalkowski, N., Cano, M., Handa, J. T. (2013) Decreased membrane complement regulators in the retinal pigmented epithelium contributes to age-related macular degeneration. J. Pathol. 229, 729-742.
139. Skerka, C., Lauer, N., Weinberger, A. A., Keilhauer, C. N., Sühnel, J., Smith, R., Schlötzer-Schrehardt, U., Fritsche, L., Heinen, S., Hartmann, A., Weber, B. H., Zipfel, P. F. (2007) Defective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration. Mol. Immunol. 44, 3398-3406.
140. Clark, S. J., Bishop, P. N., Day, A. J. (2010) Complement factor H and age-related macular degeneration: the role of glycosaminoglycan recognition in disease pathology. Biochem. Soc. Trans. 38, 1342-1348.
141. Shaw, P. X., Zhang, L., Zhang, M., Du, H., Zhao, L., Lee, C., Grob, S., Lim, S. L., Hughes, G., Lee, J., Bedell, M., Nelson, M. H., Lu, F., Krupa, M., Luo, J., Ouyang, H., Tu, Z., Su, Z., Zhu, J., Wei, X., Feng, Z., Duan, Y., Yang, Z., Ferreyra, H., Bartsch, D. U., Kozak, I., Zhang, L., Lin, F., Sun, H., Feng, H., Zhang, K. (2012) Complement factor H genotypes impact risk of age-related macular degeneration by interaction with oxidized phospholipids. Proc. Natl. Acad. Sci. USA 109, 13757-13762.
142. Geissmann, F., Jung, S., Littman, D. R. (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71-82.
143. Vessey, K. A., Greferath, U., Jobling, A. I., Phipps, J. A., Ho, T., Waugh, M., Fletcher, E. L. (2012) Ccl2/Cx3cr1 knock-out mice have inner retinal dysfunction but are not an accelerated model of AMD. Invest. Ophthalmol. Vis. Sci. 53, 7833-7846.
144. Sennlaub, F., Auvynet, C., Calippe, B., Lavalette, S., Poupel, L., Hu, S. J., Dominguez, E., Camelo, S., Levy, O., Guyon, E., Saederup, N., Charo, I. F., Rooijen, N. V., Nandrot, E., Bourges, J. L., Behar-Cohen, F., Sahel, J. A., Guillonneau, X., Raoul, W., Combadiere, C. (2013) CCR2(+) monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice. EMBO Mol. Med. 5, 1775-1793.
145. Hu, S. J., Calippe, B., Lavalette, S., Roubeix, C., Montassar, F., Housset, M., Levy, O., Delarasse, C., Paques, M., Sahel, J. A., Sennlaub, F., Guillonneau, X. (2015) Upregulation of P2RX7 in Cx3cr1-deficient mononuclear phagocytes Lleads to increased interleukin-1b secretion and photoreceptor neurodegeneration. J. Neurosci. 35, 6987-6996.
146. Mizutani, M., Pino, P. A., Saederup, N., Charo, I. F., Ransohoff, R. M., Cardona, A. E. (2012) The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J. Immunol. 188, 29-36.
147. Tuo, J., Smith, B. C., Bojanowski, C. M., Meleth, A. D., Gery, I., Csaky, K. G., Chew, E. Y., Chan, C. C. (2004) The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age-related macular degeneration. FASEB J. 18, 1297-1299.
148. Scholl, H. P., Charbel Issa, P., Walier, M., Janzer, S., Pollok-Kopp, B., Börncke, F., Fritsche, L. G., Chong, N. V., Fimmers, R., Wienker, T., Holz, F. G., Weber, B. H., Oppermann, M. (2008) Systemic complement activation in age-related macular degeneration. PLoS One 3, e2593.
149. Machalińska, A., Dziedziejko, V., Mozolewska-Piotrowska, K., Karczewicz, D., Wiszniewska, B., Machaliński, B. (2009) Elevated plasma levels of C3a complement compound in the exudative form of agerelated macular degeneration. Ophthalmic Res. 42, 54-59.
150. Seddon, J. M., Gensler, G., Milton, R. C., Klein, M. L., Rifai, N. (2004) Association between C-reactive protein and age-related macular degeneration. JAMA 291, 704-710.
151. Kikuchi, M., Nakamura, M., Ishikawa, K., Suzuki, T., Nishihara, H., Yamakoshi, T., Nishio, K., Taki, K., Niwa, T., Hamajima, N., Terasaki, H. (2007) Elevated C-reactive protein levels in patients with polypoidal choroidal vasculopathy and patients with neovascular age-related macular degeneration. Ophthalmology 114, 1722-1727.
152. Min, J. K., Kim, J., Woo, J. M. (2015) Elevated plasma pentraxin3 levels and its association with neovascular age-related macular degeneration. Ocul. Immunol. Inflamm. 23, 205-211.
153. Cherepanoff, S., Mitchell, P., Wang, J. J., Gillies, M. C. (2006) Retinal autoantibody profile in early age-related macular degeneration: preliminary findings from the Blue Mountains Eye Study. Clin. Experiment. Ophthalmol. 34, 590-595.
154. Gu, X., Meer, S. G., Miyagi, M., Rayborn, M. E., Hollyfield, J. G., Crabb, J. W., Salomon, R. G. (2003) Carboxyethylpyrrole protein adducts and autoantibodies, biomarkers for age-related macular degeneration. J. Biol. Chem. 278, 42027-42035.
155. Hoffman, M., Blum, A., Baruch, R., Kaplan, E., Benjamin, M. (2004) Leukocytes and coronary heart disease. Atherosclerosis 172, 1-6.
156. Smith, W., Mitchell, P., Leeder, S. R., Wang, J. J. (1998) Plasma fibrinogen levels, other cardiovascular risk factors, and age-related maculopathy: the Blue Mountains Eye Study. Arch. Ophthalmol. 116, 583-587.
157. Shankar, A., Mitchell, P., Rochtchina, E., Tan, J., Wang, J. J. (2007) Association between circulating white blood cell count and long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Am. J. Epidemiol. 165, 375-382.
158. Ilhan, N., Daglioglu, M. C., Ilhan, O., Coskun, M., Tuzcu, E. A., Kahraman, H., Keskin, U. (2014) The significance of the neutrophil/ lymphocyte ratio as a simple indicator of inflammation in age-related macular degeneration. Ocul. Immunol. Inflamm., 1-2.
159. Ozgonul, C., Sertoglu, E. (2014) Accurate use of neutrophil/ lymphocyte ratio in patients with age-related macular degeneration. Ocul. Immunol. Inflamm., 1-2.
160. Nassar, K., Grisanti, S., Elfar, E., Lüke, J., Lüke, M., Grisanti, S. (2015) Serum cytokines as biomarkers for age-related macular degeneration. Graefes Arch. Clin. Exp. Ophthalmol. 253, 699-704.
161. Liu, B., Wei, L., Meyerle, C., Tuo, J., Sen, H. N., Li, Z., Chakrabarty, S., Agron, E., Chan, C. C., Klein, M. L., Chew, E., Ferris, F., Nussenblatt, R. B. (2011) Complement component C5a promotes expression of IL-22 and IL-17 from human T cells and its implication in age-related macular degeneration. J. Transl. Med. 9, 1-12.
162. Shin, J. I., Bayry, J. (2013) A role for IL-17 in age-related macular degeneration. Nat. Rev. Immunol. 13, 701.
163. Starr, C., Taggart, R. (1989) Biology: The Unity and Diversity of Life. Wadsworth, Belmont, CA, USA, 398.
164. Swanson, M. W., McGwin, Jr., G. (2008) Anti-inflammatory drug use and age-related macular degeneration. Optom. Vis. Sci. 85, 947-950.
165. McGeer, P. L., Sibley, J. (2005) Sparing of age-related macular degeneration in rheumatoid arthritis. Neurobiol. Aging 26, 1199-1203.
166. Nussenblatt, R. B., Byrnes, G., Sen, H. N., Yeh, S., Faia, L., Meyerle, C., Wroblewski, K., Li, Z., Liu, B., Chew, E., Sherry, P. R., Friedman, P., Gill, F., Ferris III, F. (2010) A randomized pilot study of systemic immunosuppression in the treatment of age-related macular degeneration with choroidal neovascularization. Retina 30, 1579-1587.
167. Flaxel, C., Schain, M. B., Hamon, S. C., Francis, P. J. (2012) Prospective randomized controlled trial of combination ranibizumab (Lucentis) and bromfenac (Xibrom) for neovascular age-related macular degeneration: a pilot study. Retina 32, 417-423.
168. Gomi, F., Sawa, M., Tsujikawa, M., Nishida, K. (2012) Topical bromfenac as an adjunctive treatment with intravitreal ranibizumab for exudative age-related macular degeneration. Retina 32, 1804-1810.
169. Ye, J., Xu, Y. F., He, J. J., Lou, L. X. (2014) Association between aspirin use and age-related macular degeneration: a meta-analysis. Invest. Ophthalmol. Vis. Sci. 55, 2687-2696.
170. Li, L., Li, W., Chen, C. Z., Yi, Z. H., Zhou, Y. Y. (2015) Is aspirin use associated with age-related macular degeneration? A meta-analysis. J. Clin. Pharm. Ther. 40, 144-154.
171. Mian, M. F., Lauzon, N. M., Stämpfli, M. R., Mossman, K. L., Ashkar, A. A. (2008) Impairment of human NK cell cytotoxic activity and cytokine release by cigarette smoke. J. Leukoc. Biol. 83, 774-784.
172. Van Kampen, E., Jaminon, A., van Berkel, T. J., Van Eck, M. (2014) Dietinduced (epigenetic) changes in bone marrow augment atherosclerosis. J. Leukoc. Biol. 96, 833-841.
173. Wallace, F. A., Miles, E. A., Evans, C., Stock, T. E., Yaqoob, P., Calder, P. C. (2001) Dietary fatty acids influence the production of Th1- but not Th2-type cytokines. J. Leukoc. Biol. 69, 449-457.
174. Desai, A., Grolleau-Julius, A., Yung, R. (2010) Leukocyte function in the aging immune system. J. Leukoc. Biol. 87, 1001-1009.
175. Butcher, S. K., Chahal, H., Nayak, L., Sinclair, A., Henriquez, N. V., Sapey, E., O'Mahony, D., Lord, J. M. (2001) Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J. Leukoc. Biol. 70, 881-886.
176. Singh, A., Faber, C., Falk, M., Nissen, M. H., Hviid, T. V., Sørensen, T. L. (2012) Altered expression of CD46 and CD59 on leukocytes in neovascular age-related macular degeneration. Am. J. Ophthalmol. 154, 193-199.e2.
177. Grunin, M., Burstyn-Cohen, T., Hagbi-Levi, S., Peled, A., Chowers, I. (2012) Chemokine receptor expression in peripheral blood monocytes from patients with neovascular age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 53, 5292-5300.
178. Falk, M. K., Singh, A., Faber, C., Nissen, M. H., Hviid, T., Sørensen, T. L. (2014) Dysregulation of CXCR3 expression on peripheral blood leukocytes in patients with neovascular age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 55, 4050-4056.
179. Singh, A., Falk, M. K., Hviid, T. V., Sørensen, T. L. (2013) Increased expression of CD200 on circulating CD11b+ monocytes in patients with neovascular age-related macular degeneration. Ophthalmology 120, 1029-1037.
180. Bhutto, I., Lutty, G. (2012) Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane/choriocapillaris complex. Mol. Aspects Med. 33, 295-317.