Drusen complement components C3a and C5a promote choroidal neovascularization

Nozaki, Miho; Raisler, Brian J.; Sakurai, Eiji; Sarma, J. Vidya; Barnum, Scott R.; Lambris, John D.; Chen, Yali; Zhang, Kang; Ambati, Balamurali K.; Baffi, Judit Z.; Ambati, Jayakrishna

doi:10.1073/pnas.0408835103

Cited by 650Retinal Diseases and TreatmentsComplement system in diseasesOcular Diseases and Behçet’s Syndrome

Drusen complement components C3a and C5a promote choroidal neovascularization

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Nozaki, Miho, Raisler, Brian J., Sakurai, Eiji, Sarma, J. Vidya, Barnum, Scott R., Lambris, John D., Chen, Yali, Zhang, Kang +3 more·2006·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0408835103PMC PMC1413680

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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.

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Several experiments using mouse models of laser-induced CNV have demonstrated that all complement pathways, particularly the alternative and terminal pathways, play a significant role in angiogenesis.
“Several experiments using mouse models of laser-induced CNV have demonstrated that all complement pathways, particularly the alternative and terminal pathways, play a significant role in angiogenesis [150,152,153,154,155,156,157,158,159,160,161,162,163].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [156]

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Authors: Nozaki, M., Raisler, B. J., Sakurai, E., Sarma, J. V., Barnum, S. R., Lambris, J. D., Chen, Y., Zhang, K., Ambati, B. K., Baffi, J. Z., & Ambati, J.
Affiliations: University of Kentucky (US)
University of Michigan (US)
University of Alabama at Birmingham (US)
University of Pennsylvania (US)
University of Utah (US)
Augusta University (US)
ORCID: Nozaki, Miho
Barnum, Scott R.
Lambris, John D.
Chen, Yali
Zhang, Kang
Ambati, Balamurali K.
Ambati, Jayakrishna
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2006-02
Volume: 103
Issue: 7
Pages: 2328-2333
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0408835103
PMC: PMC1413680
OpenAlex: W1977327764
Cited by: 650
References: 51
Citations by year: 2026: 16 · 2025: 24 · 2024: 28 · 2023: 38 · 2022: 34 · 2021: 40 · 2020: 32 · 2019: 20 · 2018: 37 · 2017: 31 · 2016: 32 · 2015: 44 · 2014: 37 · 2013: 32 · 2012: 45
FWCI: 26.52
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed (publishedVersion)
Funders: John A. Hartford Foundation
American Health Assistance Foundation
Foundation Fighting Blindness
Hartford Foundation for Public Giving
Ronald McDonald House Charities
International Retinal Research Foundation
Karl Kirchgessner Foundation
Research to Prevent Blindness
Macula Vision Research Foundation
Deutsches Krebsforschungszentrum
E. Matilda Ziegler Foundation for the Blind
National Institutes of Health (1t32dc000065-01, GM62134, M01-RR00064)
National Eye Institute (R01EY014448, R01EY015422, R01EY014428, EY14448, EY14428, P30EY014800, EY-15422)
National Institute on Deafness and Other Communication Disorders (5T32DC00065, T32-DC000065)
National Institute of General Medical Sciences (GM-62134, R24GM069736, R01GM062134, GM69736)
National Center for Research Resources (M01-RR 00064, M01RR000064)
Topics: Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
Keywords: drusen, choroidal neovascularization, age-related macular degeneration, complement C3a, C5a, VEGF expression, retinal pigment epithelium, laser-induced CNV, leukocyte recruitment, angiogenesis, therapeutic target
MeSH terms: Aged, 80 and over, Animals, Female, Humans, Macular Degeneration, Male, Mice, Mutant Strains, Retinal Drusen, Complement C3a, Complement C5a, Choroidal Neovascularization, Vascular Endothelial Growth Factor A, Mice

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Drusen complement components C3a and C5a promote choroidal neovascularization

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