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

Abstract

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.

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Figure 1: Ccl2−/− and Ccr2−/− mice develop early AMD.
Figure 2: Ccl2−/− and Ccr2−/− mice develop retinal degeneration.
Figure 3: Ccl2−/− and Ccr2−/− mice develop neovascular AMD and overexpress VEGF in RPE.
Figure 4: Complement and IgG deposition can stimulate Ccl-2 and VEGF secretion.
Figure 5: Ccl-2 overexpression and macrophage infiltration in aged wild-type mice.
Figure 6: Macrophages are immobilized by, adhere to and degrade C5 and IgG.

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Acknowledgements

We thank M.G. Engle, M. Jennes and R. King for assistance with histology and electron microscopy; G. Chen for maintaining cell cultures; M.H. Hanson for photography; J. Husemann for technical advice; H.E. Grossniklaus for expertise in interpreting electron micrographs; and A.P. Adamis, S. Bondada, D.C. Collins, R. Mohan, E.J. Smart, V. Kumar, P.A. Pearson, A.M. Rao, G.S. Rao and J.G. Woodward for valuable discussions. J.A. was supported by a Foundation Fighting Blindness Career Development Award, the Dennis W. Jahnigen Career Development Award administered by the American Geriatrics Society and funded by the John A. Hartford Foundation and Atlantic Philanthropies, grants from Prevent Blindness America and Fight for Sight and a physician-scientist award from University of Kentucky; E.S. was supported by a Fight For Sight postdoctoral fellowship; and B.K.A. was supported by a Knights-Templar Eye Foundation grant.

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Correspondence to Jayakrishna Ambati.

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J.A. is listed on an initial patent filing by the University of Kentucky, describing the findings in these mice.

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Ambati, J., Anand, A., Fernandez, S. et al. An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Nat Med 9, 1390–1397 (2003). https://doi.org/10.1038/nm950

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