May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
CCR3 and Eotaxins are Specific Neovascular Targets in Age-Related Macular Degeneration
Author Affiliations & Notes
  • J. Z. Baffi
    Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky
  • A. Takeda
    Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky
  • M. Nozaki
    Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky
  • W. Cho
    Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky
  • M. E. Kleinman
    Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky
  • S. Grisanti
    Eye Hospital at the Centre for Ophthalmology, Eberhard-Karls University, Tuebingen, Germany
  • M. E. Rothenberg
    Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
  • J. Ambati
    Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky
  • Footnotes
    Commercial Relationships  J.Z. Baffi, None; A. Takeda, None; M. Nozaki, None; W. Cho, None; M.E. Kleinman, None; S. Grisanti, None; M.E. Rothenberg, None; J. Ambati, None.
  • Footnotes
    Support  NEI/NIH, Research to Prevent Blindness, Burroughs Wellcome Fund, American Health Assistance Foundation
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 1538. doi:https://doi.org/
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    • Get Citation

      J. Z. Baffi, A. Takeda, M. Nozaki, W. Cho, M. E. Kleinman, S. Grisanti, M. E. Rothenberg, J. Ambati; CCR3 and Eotaxins are Specific Neovascular Targets in Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1538. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : To understand the role of CCR3 in angiogenesis. Age-related macular degeneration (AMD) ) is a leading cause of blindness worldwide. The principal cause of severe vision loss in patients with AMD is choroidal neovascularization (CNV).

Methods: : Immunohistochemical analyses were conducted on CNV tissue of patients with and without AMD, and tube formation assay on human choroidal endothelial cells (CECs). CNV was induced in various genetically modified and their background mice by laser injury and volumes measured by confocal evaluation of Isolectin B4 staining of RPE-choroid flatmounts following neutralizing antibodies, small molecule antagonist or control IgG injections.

Results: : Here we report the first molecular marker specific for human choroidal endothelial cells in patients with CNV as the chemokine receptor CCR3. We also show that all eotaxins-1, 2, and 3 are expressed in human CNV. We also show that CCR3 and its ligands eotaxin-1 (CCL11) and eotaxin-2 (CCL24) are required for the development of laser injury-induced CNV in mice, an accelerated model of neovascular AMD. CNV was inhibited in Ccr3–/–, Ccl11–/–, Ccl24–/– and Ccl11×Ccl24–/– mice as well as by neutralizing antibodies against CCR3, CCL11, and CCL24, and a small molecule CCR3 antagonist in wild-type mice. CNV was not associated with eosinophil recruitment or mast cell homing, the function traditionally assigned to CCR3, nor was CNV inhibited in Δdbl GATA (eosinophil deficient) or KitWv/KitWv (mast cell deficient) mice. CCR3 blockade did not affect macrophage infiltration, which promotes CNV development, but instead reduced choroidal endothelial cell (CEC) proliferation in mice in vivo and inhibited human CEC tube formation in vitro.

Conclusions: : These findings identify CCR3 as a novel molecular target in CNV due to AMD. These data also provide a strategy to molecularly uncouple the intricately interwoven phenomena of inflammation and angiogenesis.

Keywords: age-related macular degeneration • choroid: neovascularization • cytokines/chemokines 
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