7-Ketocholesterol Increases Retinal Microglial Migration, Activation, and Angiogenicity: A Potential Pathogenic Mechanism Underlying Age-related Macular Degeneration

Scientific Reports

Volumn 5, Issue , 2015, Pages 1-10

  Indaram, Maanasa ^a   Ma, Wenxin ^a   Zhao, Lian ^a   Fariss, Robert N ^a   Rodriguez, Ignacio R ^a   Wong, Wai T ^a  

^a NATIONAL INSTITUTES OF HEALTH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

7-KETOCHOLESTEROL; CHEMOKINE RECEPTOR; CHEMOTACTIC FACTOR; CHOLESTEROL DERIVATIVE; CX3CR1 PROTEIN, MOUSE; NERVE GROWTH FACTOR;

ANIMAL; CELL PROLIFERATION; CELL SURVIVAL; DISEASE MODEL; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETICS; IMMUNOLOGY; MACULAR DEGENERATION; METABOLISM; MICROGLIA; MOUSE; NEOVASCULARIZATION (PATHOLOGY); PATHOLOGY; RETINA; TRANSGENIC MOUSE;

ANIMALS; CELL PROLIFERATION; CELL SURVIVAL; CHEMOTACTIC FACTORS; DISEASE MODELS, ANIMAL; GENE EXPRESSION REGULATION; KETOCHOLESTEROLS; MACULAR DEGENERATION; MICE; MICE, TRANSGENIC; MICROGLIA; NEOVASCULARIZATION, PATHOLOGIC; NERVE GROWTH FACTORS; RECEPTORS, CHEMOKINE; RETINA;

EID: 84925011456     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep09144     Document Type: Article

References (79)

1. Congdon, N. et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol 122, 477-85 (2004).
2. Congdon, N. G., Friedman, D. S. & Lietman, T. Important causes of visual impairment in the world today. JAMA 290, 2057-60 (2003).
3. Jager, R. D., Mieler, W. F. & Miller, J. W. Age-related macular degeneration. N Engl J Med 358, 2606-17 (2008).
4. Fritsche, L. G. et al. Seven new loci associated with age-related macular degeneration. Nat Genet 45, 433-9, 439e1-2 (2013).
5. Chen, W. et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A 107, 7401-6 (2010).
6. Neale, B. M. et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci U S A 107, 7395-400 (2010).
7. Curcio, C. A., Johnson, M., Huang, J. D. & Rudolf, M. Apolipoprotein B-containing lipoproteins in retinal aging and age-related macular degeneration. J Lipid Res 51, 451-67 (2010).
8. Curcio, C. A. et al. Esterified and unesterified cholesterol in drusen and basal deposits of eyes with age-related maculopathy. Exp Eye Res 81, 731-41 (2005).
9. Haimovici, R., Gantz, D. L., Rumelt, S., Freddo, T. F. & Small, D. M. The lipid composition of drusen, Bruch's membrane, and sclera by hot stage polarizing light microscopy. Invest Ophthalmol Vis Sci 42, 1592-9 (2001).
10. Pauleikhoff, D., Harper, C. A.,Marshall, J. & Bird, A. C. Aging changes in Bruch's membrane. A histochemical and morphologic study. Ophthalmology 97, 171-8 (1990).
11. Rodriguez, I. R., Clark, M. E., Lee, J. W. & Curcio, C. A. 7-ketocholesterol accumulates in ocular tissues as a consequence of aging and is present in high levels in drusen. Exp Eye Res (2014).
12. Spaide, R. F., Ho-Spaide, W. C., Browne, R. W. & Armstrong, D. Characterization of peroxidized lipids in Bruch's membrane. Retina 19, 141-7 (1999).
13. Baba, T. et al. A rat model for choroidal neovascularization using subretinal lipid hydroperoxide injection. Am J Pathol 176, 3085-97 (2010).
14. Tamai, K. et al. Lipid hydroperoxide stimulates subretinal choroidal neovascularization in the rabbit. Exp Eye Res 74, 301-8 (2002).
15. Lordan, S., Mackrill, J. J. & O'Brien, N. M. Oxysterols and mechanisms of apoptotic signaling: implications in the pathology of degenerative diseases. J Nutr Biochem 20, 321-36 (2009).
16. Vejux, A. & Lizard, G. Cytotoxic effects of oxysterols associated with human diseases: Induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis. Mol Aspects Med 30, 153-70 (2009).
17. Rodriguez, I. R., Alam, S. & Lee, J. W. Cytotoxicity of oxidized low-density lipoprotein in cultured RPE cells is dependent on the formation of 7-ketocholesterol. Invest Ophthalmol Vis Sci 45, 2830-7 (2004).
18. Rodriguez, I. R. & Fliesler, S. J. Photodamage generates 7-keto-and 7-hydroxycholesterol in the rat retina via a free radical-mediated mechanism. Photochem Photobiol 85, 1116-25 (2009).
19. Moreira, E. F., Larrayoz, I. M., Lee, J. W. & Rodriguez, I. R. 7-Ketocholesterol is present in lipid deposits in the primate retina: potential implication in the induction of VEGF and CNV formation. Invest Ophthalmol Vis Sci 50, 523-32 (2009).
20. Anderson, M., Dawson, W. W., Gonzalez-Martinez, J.& Curcio, C. A. Drusen and lipid-filled retinal pigment epithelium cells in a rhesus macula. Vet Ophthalmol 9, 201-7 (2006).
21. Rodriguez, I. R. & Larrayoz, I. M. Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration. J Lipid Res 51, 2847-62 (2010).
22. Amaral, J., Lee, J. W., Chou, J., Campos, M. M. & Rodriguez, I. R. 7-Ketocholesterol induces inflammation and angiogenesis in vivo: a novel rat model. PLoS One 8, e56099 (2013).
23. Huang, J. D., Amaral, J., Lee, J. W. & Rodriguez, I. R. 7-Ketocholesterol-induced inflammation signals mostly through the TLR4 receptor both in vitro and in vivo. PLoS One 9, e100985 (2014).
24. Ma, W., Coon, S., Zhao, L., Fariss, R. N. & Wong, W. T. A2E accumulation influences retinal microglial activation and complement regulation. Neurobiol Aging 34, 943-60 (2013).
25. Xu, H., Chen, M., Manivannan, A., Lois, N. & Forrester, J. V. Age-dependent accumulation of lipofuscin in perivascular and subretinal microglia in experimental mice. Aging Cell 7, 58-68 (2008).
26. Gupta, N., Brown, K. E. & Milam, A. H. Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration. Exp Eye Res 76, 463-71 (2003).
27. Combadiere, C. et al. CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J Clin Invest 117, 2920-8 (2007).
28. Ma, W., Zhao, L., Fontainhas, A. M., Fariss, R. N. &Wong, W. T. 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, e7945 (2009).
29. Tuo, J. et al. Murine ccl2/cx3cr1 deficiency results in retinal lesions mimicking human age-related macular degeneration. Invest Ophthalmol Vis Sci 48, 3827-36 (2007).
30. Chinnery, H. R. et al. Accumulation of murine subretinal macrophages: effects of age, pigmentation and CX3CR1. Neurobiol Aging 33, 1769-76 (2012).
31. Kahlenberg, J. M., Lundberg, K. C., Kertesy, S. B., Qu, Y. & Dubyak, G. R. Potentiation of caspase-1 activation by the P2X7 receptor is dependent on TLR signals and requires NF-kappaB-driven protein synthesis. J Immunol 175, 7611-22 (2005).
32. Ferrari, D. et al. Extracellular ATP triggers IL-1 beta release by activating the purinergic P2Z receptor of human macrophages. J Immunol 159, 1451-8 (1997).
33. Subramanian, N., Natarajan, K., Clatworthy, M. R., Wang, Z. & Germain, R. N. The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 153, 348-61 (2013).
34. Nakajima, K. & Kohsaka, S. Microglia: neuroprotective and neurotrophic cells in the central nervous system. Curr Drug Targets Cardiovasc Haematol Disord 4, 65-84 (2004).
35. Ueno, M. et al. Layer V cortical neurons require microglial support for survival during postnatal development. Nat Neurosci 16, 543-51 (2013).
36. Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596-609 (2013).
37. Liang, C. C., Park, A. Y. & Guan, J. L. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2, 329-33 (2007).
38. Cao, J. et al. A subretinal matrigel rat choroidal neovascularization (CNV) model and inhibition of CNV and associated inflammation and fibrosis by VEGF trap. Invest Ophthalmol Vis Sci 51, 6009-17 (2010).
39. Curcio, C. A., Johnson, M., Rudolf, M. &Huang, J. D. The oil spill in ageing Bruch membrane. Br J Ophthalmol 95, 1638-45 (2011).
40. Huang, J. D., Presley, J. B., Chimento, M. F., Curcio, C. A. & Johnson, M. Age-related changes in human macular Bruch's membrane as seen by quick-freeze/deep-etch. Exp Eye Res 85, 202-18 (2007).
41. Ruberti, J. W. et al. Quick-freeze/deep-etch visualization of age-related lipid accumulation in Bruch's membrane. Invest Ophthalmol Vis Sci 44, 1753-9 (2003).
42. Malek, G., Li, C.M., Guidry, C.,Medeiros, N. E. & Curcio, C. A. Apolipoprotein B in cholesterol-containing drusen and basal deposits of human eyes with age-related maculopathy. Am J Pathol 162, 413-25 (2003).
43. Wang, L. et al. Abundant lipid and protein components of drusen. PLoS One 5, e10329 (2010).
44. Oak, A. S., Messinger, J. D. & Curcio, C. A. Subretinal drusenoid deposits: further characterization by lipid histochemistry. Retina 34, 825-6 (2014).
45. Johnson, L. V. et al. Cell culture model that mimics drusen formation and triggers complement activation associated with age-related macular degeneration. Proc Natl Acad Sci U S A 108, 18277-82 (2011).
46. Poli, G., Biasi, F. & Leonarduzzi, G. Oxysterols in the pathogenesis of major chronic diseases. Redox Biol 1, 125-30 (2013).
47. Hahn, P., Ying, G. S., Beard, J. & Dunaief, J. L. Iron levels in human retina: sex difference and increase with age. Neuroreport 17, 1803-6 (2006).
48. Lemaire, S. et al. Different patterns of IL-1beta secretion, adhesion molecule expression and apoptosis induction in human endothelial cells treated with 7alpha-, 7beta-hydroxycholesterol, or 7-ketocholesterol. FEBS Lett 440, 434-9 (1998).
49. Luthra, S. et al . 7-Ketocholesterol activates caspases-3/7, -8, and -12 in human microvascular endothelial cells in vitro. Microvasc Res 75, 343-50 (2008).
50. Dulak, J. et al. Vascular endothelial growth factor synthesis in vascular smooth muscle cells is enhanced by 7-ketocholesterol and lysophosphatidylcholine independently of their effect on nitric oxide generation. Atherosclerosis 159, 325-32 (2001).
51. Lee, H. S. et al. TNF-alpha activates death pathway in human aorta smooth muscle cell in the presence of 7-ketocholesterol. Biochem Biophys Res Commun 333, 1093-9 (2005).
52. Berthier, A. et al. 7-Ketocholesterol-induced apoptosis. Involvement of several pro-apoptotic but also anti-apoptotic calcium-dependent transduction pathways. FEBS J 272, 3093-104 (2005).
53. Hayden, J.M. et al. Induction of monocyte differentiation and foam cell formation in vitro by 7-ketocholesterol. J Lipid Res 43, 26-35 (2002).
54. Larrayoz, I. M., Huang, J. D., Lee, J. W., Pascual, I. & Rodriguez, I. R. 7-ketocholesterol-induced inflammation: involvement of multiple kinase signaling pathways via NFkappaB but independently of reactive oxygen species formation. Invest Ophthalmol Vis Sci 51, 4942-55 (2010).
55. Kumar, A., Zhao, L., Fariss, R. N., McMenamin, P. G. & Wong, W. T. Vascular associations and dynamic process motility in perivascular myeloid cells of the mouse choroid: implications for function and senescent change. Invest Ophthalmol Vis Sci 55, 1787-96 (2014).
56. Eibinger, G. et al. On the role of 25-hydroxycholesterol synthesis by glioblastoma cell lines. Implications for chemotactic monocyte recruitment. Exp Cell Res 319, 1828-38 (2013).
57. Raccosta, L. et al. The oxysterol-CXCR2 axis plays a key role in the recruitment of tumor-promoting neutrophils. J Exp Med 210, 1711-28 (2013).
58. Palozza, P. et al. Redox regulation of 7-ketocholesterol-induced apoptosis by beta-carotene in human macrophages. Free Radic Biol Med 42, 1579-90 (2007).
59. Pedruzzi, E. et al. NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells. Mol Cell Biol 24, 10703-17 (2004).
60. Shimozawa, M. et al. 7-Ketocholesterol enhances the expression of adhesion molecules on human aortic endothelial cells by increasing the production of reactive oxygen species. Redox Rep 9, 370-5 (2004).
61. Marneros, A. G. NLRP3 inflammasome blockade inhibits VEGF-A-induced age-related macular degeneration. Cell Rep 4, 945-58 (2013).
62. Tarallo, V. et al. DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell 149, 847-59 (2012).
63. Tseng, W. A. et al. NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci 54, 110-20 (2013).
64. Favret, S. et al . Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions. Aging (Albany NY) 5, 427-44 (2013).
65. Huang, H., Parlier, R., Shen, J. K., Lutty, G. A. & Vinores, S. A. VEGF receptor blockade markedly reduces retinal microglia/macrophage infiltration into laser-induced CNV. PLoS One 8, e71808 (2013).
66. Krause, T. A., Alex, A. F., Engel, D. R., Kurts, C. & Eter, N. VEGF-production by CCR2-dependent macrophages contributes to laser-induced choroidal neovascularization. PLoS One 9, e94313 (2014).
67. Sennlaub, F. et al. CCR2(1) 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, 1775-93 (2013).
68. Fogerty, J. & Besharse, J. C. Subretinal infiltration of monocyte derived cells and complement misregulation in mice with AMD-like pathology. Adv Exp Med Biol 801, 355-63 (2014).
69. Omri, S. et al.Microglia/macrophages migrate through retinal epithelium barrier by a transcellular route in diabetic retinopathy: role of PKCzeta in the Goto Kakizaki rat model. Am J Pathol 179, 942-53 (2011).
70. Freund, K. B., Zweifel, S. A. & Engelbert, M. Do we need a new classification for choroidal neovascularization in age-related macular degeneration? Retina 30, 1333-49 (2010).
71. Grossniklaus, H. E. & Green, W. R. Choroidal neovascularization. Am J Ophthalmol 137, 496-503 (2004).
72. Yannuzzi, L. A. et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 21, 416-34 (2001).
73. Jung, S. et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20, 4106-14 (2000).
74. Mattapallil, M. J. et al. The Rd8 mutation of the Crb1 gene is present in vendor lines of C57BL/6N mice and embryonic stem cells, and confounds ocular induced mutant phenotypes. Invest Ophthalmol Vis Sci 53, 2921-7 (2012).
75. Tan, E. et al . Expression of cone-photoreceptor-specific antigens in a cell line derived from retinal tumors in transgenic mice. Invest Ophthalmol Vis Sci 45, 764-8 (2004).
76. Damani, M. R. et al. Age-related alterations in the dynamic behavior of microglia. Aging Cell 10, 263-76 (2011).
77. Lampugnani, M. G. Cell migration into a wounded area in vitro. Methods Mol Biol 96, 177-82 (1999).
78. Zhao, L., Ma, W., Fariss, R. N. & Wong, W. T. Minocycline attenuates photoreceptor degeneration in a mouse model of subretinal hemorrhage microglial: inhibition as a potential therapeutic strategy. Am J Pathol 179, 1265-77 (2011).
79. Li, Y. et al. Direct labeling and visualization of blood vessels with lipophilic carbocyanine dye DiI. Nat Protoc 3, 1703-8 (2008).