title: Drusen complement components C3a and C5a promote choroidal neovascularization.
abstract: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in industrialized nations, affecting 30-50 million people worldwide. The earliest clinical hallmark of AMD is the presence of drusen, extracellular deposits that accumulate beneath the retinal pigmented epithelium. Although drusen nearly always precede and increase the risk of choroidal neovascularization (CNV), the late vision-threatening stage of AMD, it is unknown whether drusen contribute to the development of CNV. Both in patients with AMD and in a recently described mouse model of AMD, early subretinal pigmented epithelium deposition of complement components C3 and C5 occurs, suggesting a contributing role for these inflammatory proteins in the development of AMD. Here we provide evidence that bioactive fragments of these complement components (C3a and C5a) are present in drusen of patients with AMD, and that C3a and C5a induce VEGF expression in vitro and in vivo. Further, we demonstrate that C3a and C5a are generated early in the course of laser-induced CNV, an accelerated model of neovascular AMD driven by VEGF and recruitment of leukocytes into the choroid. We also show that genetic ablation of receptors for C3a or C5a reduces VEGF expression, leukocyte recruitment, and CNV formation after laser injury, and that antibody-mediated neutralization of C3a or C5a or pharmacological blockade of their receptors also reduces CNV. Collectively, these findings establish a mechanistic basis for the clinical observation that drusen predispose to CNV, revealing a role for immunological phenomena in angiogenesis and providing therapeutic targets for AMD.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Miho
authors.initials: M
authors.lastname: Nozaki
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Raisler
authors.forename: Eiji
authors.initials: E
authors.lastname: Sakurai
authors.forename: J Vidya
authors.initials: JV
authors.lastname: Sarma
authors.forename: Scott R
authors.initials: SR
authors.lastname: Barnum
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.forename: Yali
authors.initials: Y
authors.lastname: Chen
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
authors.forename: Judit Z
authors.initials: JZ
authors.lastname: Baffi
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
mesh_terms: D000369:Aged, 80 and over; D000818:Animals; D020256:Choroidal Neovascularization / Q000235:genetics / Q000378:metabolism*; D015926:Complement C3a / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015936:Complement C5a / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D015593:Retinal Drusen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D015926:Complement C3a; D015936:Complement C5a