title: CCR3 is a target for age-related macular degeneration diagnosis and therapy.
abstract: Age-related macular degeneration (AMD), a leading cause of blindness worldwide, is as prevalent as cancer in industrialized nations. Most blindness in AMD results from invasion of the retina by choroidal neovascularisation (CNV). Here we show that the eosinophil/mast cell chemokine receptor CCR3 is specifically expressed in choroidal neovascular endothelial cells in humans with AMD, and that despite the expression of its ligands eotaxin-1, -2 and -3, neither eosinophils nor mast cells are present in human CNV. Genetic or pharmacological targeting of CCR3 or eotaxins inhibited injury-induced CNV in mice. CNV suppression by CCR3 blockade was due to direct inhibition of endothelial cell proliferation, and was uncoupled from inflammation because it occurred in mice lacking eosinophils or mast cells, and was independent of macrophage and neutrophil recruitment. CCR3 blockade was more effective at reducing CNV than vascular endothelial growth factor A (VEGF-A) neutralization, which is in clinical use at present, and, unlike VEGF-A blockade, is not toxic to the mouse retina. In vivo imaging with CCR3-targeting quantum dots located spontaneous CNV invisible to standard fluorescein angiography in mice before retinal invasion. CCR3 targeting might reduce vision loss due to AMD through early detection and therapeutic angioinhibition.
authors.affiliation: Department of Ophthalmology & Visual Science, University of Kentucky, Lexington, Kentucky 40506, USA.
authors.forename: Atsunobu
authors.initials: A
authors.lastname: Takeda
authors.forename: Judit Z
authors.initials: JZ
authors.lastname: Baffi
authors.forename: Mark E
authors.initials: ME
authors.lastname: Kleinman
authors.forename: Won Gil
authors.initials: WG
authors.lastname: Cho
authors.forename: Miho
authors.initials: M
authors.lastname: Nozaki
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yamada
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kaneko
authors.forename: Romulo J C
authors.initials: RJ
authors.lastname: Albuquerque
authors.forename: Sami
authors.initials: S
authors.lastname: Dridi
authors.forename: Kuniharu
authors.initials: K
authors.lastname: Saito
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Raisler
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Budd
authors.forename: Pete
authors.initials: P
authors.lastname: Geisen
authors.forename: Ariel
authors.initials: A
authors.lastname: Munitz
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
authors.forename: Martha G
authors.initials: MG
authors.lastname: Green
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ishibashi
authors.forename: John D
authors.initials: JD
authors.lastname: Wright
authors.forename: Alison A
authors.initials: AA
authors.lastname: Humbles
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Gerard
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ogura
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Pan
authors.forename: Justine R
authors.initials: JR
authors.lastname: Smith
authors.forename: Salvatore
authors.initials: S
authors.lastname: Grisanti
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Hartnett
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000037:antagonists & inhibitors / Q000378:metabolism; D054423:Chemokine CCL24 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000378:metabolism; D002829:Choroid / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000175:diagnosis / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007962:Leukocytes; D008024:Ligands; D008268:Macular Degeneration / Q000175:diagnosis* / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D045663:Quantum Dots; D054397:Receptors, CCR3 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012160:Retina / Q000187:drug effects / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: C120429:CCL26 protein, human; C515350:CCR3 protein, human; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D054423:Chemokine CCL24; D000075906:Chemokine CCL26; D019742:Chemokines, CC; D008024:Ligands; D054397:Receptors, CCR3; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A