Cited by 37Retinal Diseases and TreatmentsComplement system in diseasesOcular Diseases and Behçet’s Syndrome

Local production of the alternative pathway component factor B is sufficient to promote laser-induced choroidal neovascularization

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Schnabolk, Gloriane, Coughlin, Beth, Joseph, Kusumam, Kunchithapautham, Kannan, Bandyopadhyay, Mausumi, O'Quinn, Elizabeth C., Nowling, Tamara, Rohrer, Bärbel·2015·Investigative Opthalmology & Visual Science

Abstract

PURPOSE: Complement factor B (CFB) is a required component of the alternative pathway (AP) of complement, and CFB polymorphisms are associated with age-related macular degeneration (AMD) risk. Complement factor B is made in the liver, but expression has also been detected in retina and retinal pigment epithelium (RPE)-choroid. We investigated whether production of CFB by the RPE can promote AP activation in mouse choroidal neovascularization (CNV). METHODS: Transgenic mice expressing CFB under the RPE65 promoter were generated and crossed onto factor B-deficient (CFB-KO) mice. Biological activity was determined in vitro using RPE monolayers and in vivo using laser-induced CNV. Contribution of systemic CFB was investigated using CFB-KO reconstituted with CFB-sufficient serum. RESULTS: Transgenic mice (CFB-tg) expressed CFB in RPE-choroid; no CFB was detected in serum. Cultured CFB-tg RPE monolayers secreted CFB apically and basally upon exposure to oxidative stress that was biologically active. Choroidal neovascularization sizes were comparable between wild-type and CFB-tg mice, but significantly increased when compared to lesions in CFB-KO mice. Injections of CFB-sufficient serum into CFB-KO mice resulted in partial reconstitution of systemic AP activity and significantly increased CNV size. CONCLUSIONS: Mouse RPE cells express and secrete CFB sufficient to promote RPE damage and CNV. This further supports that local complement production may regulate disease processes; however, the reconstitution experiments suggest that additional components may be sequestered from the bloodstream. Understanding the process of ocular complement production and regulation will further our understanding of the AMD disease process and the requirements of a complement-based therapeutic.

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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].”

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Authors
Schnabolk, G., Coughlin, B., Joseph, K., Kunchithapautham, K., Bandyopadhyay, M., O'Quinn, E. C., Nowling, T., & Rohrer, B.
Affiliations
  • Ralph H. Johnson VA Medical Center (US)
  • Medical University of South Carolina (US)
  • Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina, United States
Corresponding author
Rohrer, Bärbel
Venue
Investigative Opthalmology & Visual Science
Published
2015-03-31
Volume
56
Issue
3
Pages
1850
ISSN
  • 0146-0404 (ISSN-L)
  • 1552-5783
OpenAlex
W2063236831
Cited by
37
References
53
Citations by year
2025: 3 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 7 · 2019: 1 · 2018: 5 · 2017: 7 · 2016: 3 · 2015: 1
FWCI
5.13
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • Investigative Ophthalmology & Visual Science (publishedVersion, public-domain)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 RX000444)
  • Research to Prevent Blindness
  • Medical University of South Carolina
  • Arnold and Mabel Beckman Initiative for Macular Research
  • University of South Carolina
  • National Institutes of Health (1c06rr015455-01a1)
  • National Eye Institute (R01EY019320, R01EY024581)
  • National Cancer Institute (CO6RR015455)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R03AR053376)
  • National Center for Research Resources (C06 RR-015455)
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
factor B, alternative complement pathway, choroidal neovascularization, retinal pigment epithelium, age-related macular degeneration, oxidative stress, laser-induced CNV, transgenic mice
MeSH terms
Animals, Cells, Cultured, Choroid, Complement Pathway, Alternative, Disease Models, Animal, Electroretinography, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Lasers, Mice, Inbred C57BL, Mice, Transgenic, Complement Factor B, RNA, Messenger, Blotting, Western, Choroidal Neovascularization, Tomography, Optical Coherence, Mice, Retinal Pigment Epithelium, Real-Time Polymerase Chain Reaction

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