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.

An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation

“…A two-to threefold increase in the accumulation of ApoE E3 over ApoE E4 has been observed in various cell types [Ji et al, 2002]. If mechanisms for proper clearance in the retina and Bruch's membrane are not in place, this accumulation may serve as a pathogenic basis for disease development [Ambati et al, 2003;Tuo et al, 2004b]. In fact, the increased accumulation in non-E4 carriers may explain why ApoE is such a ubiquitous component of ocular drusen in AMD-afflicted eyes [Crabb et al, 2002].…”

“…Over-expression of VEGF in the RPE, even if only temporarily, is sufficient to induce choroidal neovascularization in the rat eye [Kliffen et al, 1997;Spilsbury et al, 2000]. CCL2 also has been associated with further deterioration and degeneration, especially in advanced disease stages [Ambati et al, 2003]. Considering that our data show nearly a twofold greater suppression of CCL2 mRNA and protein expression by E4 in RPE cells with similar findings for VEGF, we suggest that investigating the varied effects of the ApoE isoforms on chemokine and cytokine regulation may offer insights into the mechanisms responsible for the observed protective role of the E4 isoform.…”

CCR2 mediates increases in glial activation caused by exposure to HIV-1 Tat and opiates

“…Wild type [CCR2(+/+)] and CCR2(−/−) mice on a C57Bl/J6 background were used to explore the role of CCR2 in mediating Tat or morphine and Tat-induced increases in macrophages/microglia or astroglia, which were maintained and characterized as previously described (Ambati et al, 2003). To assess the selectivity of Tat 1-72 , the effects of intrastriatal Tat 1-72 , a minimally toxic, deletion mutant variant of Tat 1-72 (Tat Δ31-61 ), and saline injections were compared in CCR2(+/+) and CCR2(−/−) C57Bl/J6 mice.…”

Vascular endothelial growth factor in eye disease

“…VEGF is found in RPE in surgically excised human AMD specimens of CNV (Lopez et al, 1996;Frank et al, 1996;Grossniklaus et al, 2002). VEGF has been localized to CNV in rodent models of laserinduced CNV (Bora et al, 2005;Yi et al, 1997) and genetically modified mouse models of CNV (Ambati et al, 2003). The overexpression of VEGF in RPE caused intrachoroidal neovascularization in one model (Schwesinger et al, 2001).…”

“…The murine knockout model of Ccl-2, a chemokine important in inflammation and in attracting macrophages, developed drusen, VEGF immunoreactivity, and CNV late in life (Ambati et al, 2003). The investigators proposed that lack of the Ccl-2 chemokine led to reduced recruitment of phagocytosing macrophages and reduced turnover of debris in Bruch's membrane, thus leading to drusen.…”