An animal model of age-related macular degeneration in senescent Ccl-2-or Ccr-2-deficient mice

被引:506
作者
Ambati, J
Anand, A
Fernandez, S
Sakurai, E
Lynn, BC
Kuziel, WA
Rollins, BJ
Ambati, BK
机构
[1] Univ Kentucky, Dept Ophthalmol, Lexington, KY 40536 USA
[2] Univ Kentucky, Dept Microbiol & Immunol, Lexington, KY 40506 USA
[3] Univ Kentucky, Dept Chem, Lexington, KY 40506 USA
[4] Univ Texas, Inst Mol & Cellular Biol, Austin, TX 78712 USA
[5] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA
[6] Med Coll Georgia, Dept Ophthalmol, Augusta, GA 30907 USA
关键词
D O I
10.1038/nm950
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The study and treatment of age-related macular degeneration (AMD), a leading cause of blindness, has been hampered by a lack of animal models. Here we report that mice deficient either in monocyte chemoattractant protein-1 (Ccl-2; also known as MCP-1) or its cognate C-C chemokine receptor-2 (Ccr-2) develop cardinal features of AMD, including accumulation of lipofuscin in and drusen beneath the retinal pigmented epithelium (RPE), photoreceptor atrophy and choroidal neovascularization (CNV). Complement and IgG deposition in RPE and choroid accompanies senescence in this model, as in human AMD. RPE or choroidal endothelial production of Ccl-2 induced by complement C5a and IgG may mediate choroidal macrophage infiltration into aged wild-type choroids. Wild-type choroidal macrophages degrade C5 and IgG in eye sections of Ccl2(-/-) or Ccr2(-/-) mice. Impaired macrophage recruitment may allow accumulation of C5a and IgG, which induces vascular endothelial growth factor (VEGF) production by RPE, possibly mediating development of CNV. These models implicate macrophage dysfunction in AMD pathogenesis and may be useful as a platform for validating therapies.
引用
收藏
页码:1390 / 1397
页数:8
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