An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice.
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.
Ambati
Jayakrishna
J
Department of Ophthalmology, University of Kentucky, 740 South Limestone Street, Lexington, Kentucky 40536-0284, USA. jamba2@uky.edu
Anand
Akshay
A
Fernandez
Stefan
S
Sakurai
Eiji
E
Lynn
Bert C
BC
Kuziel
William A
WA
Rollins
Barrett J
BJ
Ambati
Balamurali K
BK
D000375:Aging / Q000276:immunology / Q000378:metabolism; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015936:Complement C5a / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008268:Macular Degeneration / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012160:Retina / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D007074:Immunoglobulin G; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D015936:Complement C5a; D003165:Complement System Proteins