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A. Takeda, M. Nozaki, B.J. Raisler, J.Z. Baffi, B.K. Ambati, J. Ambati; CCR3 Blockade Suppresses Experimental Choroidal Neovascularization . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1529.
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© ARVO (1962-2015); The Authors (2016-present)
Although intraocular inflammation is not clinically apparent in age–related macular degeneration (AMD), multiple lines of evidence support an influential role for inflammation in this condition. CCR3 is a promiscuous chemokine receptor that is predominately expressed by eosinophils but also is found on other leukocytes and some endothelial and epithelial cells. The purpose of this study was to determine the role of CCR3 in CNV.
CNV was induced by laser injury in C57BL/6J and Ccr3–/– mice and volumes measured 7 days later by confocal evaluation of Griffonia simplicifolia Isolectin B4 staining of RPE–choroid flatmounts. Neutralizing antibodies (Ab) against CCR3, eotaxin (CCL–11), eotaxin–2 (CCL–24), RANTES, MCP–3 or control goat IgG or rat IgG2a were injected into the vitreous following injury. Flow cytometry was used to determine the numbers of eosinophils, mast cells and macrophages in the choroid, expression of CCR3 by various cell types in the eye, and the cell cycle state of choroidal endothelial cells (CECs) in vivo.
CCR3 expressed on CECs increased following injury. The number of eosinophils and mast cells in the choroid was unaffected by injury or CCR3 Ab. CCR3 Ab did not inhibit choroidal macrophage infiltration following injury. CCR3 Ab suppressed CNV volume in C57BL/6J mice by nearly 60% compared to control antibody. CCR3 Ab blockade inhibited proliferation of CECs in vivo. Experiments in Ccr3–/– mice confirmed these results. Of the CCR3 ligands, blockade of only eotaxin (45%) or eotaxin–2 (70%) suppressed CNV in C57BL/6J mice compared to control antibodies (all Ps<0.001). Experiments in Ccl11–/– and Ccl24–/– mice confirmed these results.
These findings demonstrate the novel observation that CCR3 promote angiogenesis not via leukocyte modulation but rather by direct effects on CECs. CCL–11, CCL–24, and CCR3 are potential new targets for neovascular AMD.
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