Sub-lytic C5b-9 induces functional changes in retinal pigment epithelial cells consistent with age-related macular degeneration
Open accessAbstract
Purpose There is evidence for complement dysfunction in age-related macular degeneration (AMD). Complement activation leads to formation of the membrane attack complex (MAC), known to assemble on retinal pigment epithelial (RPE) cells. Therefore, the effect of sub-lytic MAC on RPE cells was examined with regard to pro-inflammatory or pro-angiogenic mediators relevant in AMD.Methods For sub-lytic MAC induction, RPE cells were incubated with an antiserum to complement regulatory protein CD59, followed by normal human serum (NHS) to induce 5% cell death, measured by a viability assay. MAC formation was evaluated by immunofluorescence and FACS analysis. Interleukin (IL)-6, -8, monocytic chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) were quantified by enzyme-linked immunosorbent assay (ELISA). Intracellular MCP-1 was analysed by immunofluorescence, vitronectin by western blotting, and gelatinolytic matrix metalloproteinases (MMPs) by zymography.Results Incubation of RPE cells with the CD59 antiserum followed by 5% NHS induced sub-lytic amounts of MAC, verified by FACS and immunofluorescence. This treatment stimulated the cells to release IL-6, -8, MCP-1, and VEGF. MCP-1 staining, production of vitronectin, and gelatinolytic MMPs were also elevated in response to sub-lytic MAC.Conclusions MAC assembly on RPE cells increases the IL-6, -8, and MCP-1 production. Therefore, sub-lytic MAC might have a significant role in generating a pro-inflammatory microenvironment, contributing to the development of AMD. Enhanced vitronectin might be a protective mechanism against MAC deposition. In addition, the increased expression of gelatinolytic MMPs and pro-angiogenic VEGF may be associated with neovascular processes and late AMD.
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Sublytic levels of MAC have been shown to stimulate the release of growth factors from nucleated cells, including VEGF from RPE in cell culture studies.
“For example, sublytic levels of MAC have been shown to stimulate the release of growth factors from nucleated cells [99,100], including VEGF from RPE in cell culture studies [146,165].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [146]
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- Authors
- Lueck, K., Wasmuth, S., Williams, J., Hughes, T. R., Morgan, B. P., Lommatzsch, A., Greenwood, J., Moss, S. E., & Pauleikhoff, D.
- Affiliations
- St. Franziskus Hospital (DE)
- University College London (GB)
- Cardiff University (GB)
- Corresponding author
- Pauleikhoff, D
- Venue
- Eye
- Published
- 2011-05-20
- Volume
- 25
- Issue
- 8
- Pages
- 1074-1082
- ISSN
- 0078-5334 (ISSN-L)
- 0950-222X
- 1476-5454
- PMC
- PMC3178225
- OpenAlex
- W1966355819
- Cited by
- 80
- References
- 58
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 8 · 2023: 5 · 2022: 7 · 2021: 7 · 2020: 8 · 2019: 2 · 2018: 9 · 2017: 4 · 2016: 6 · 2015: 8 · 2014: 6 · 2013: 2 · 2012: 2
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Eye (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Deutscher Akademischer Austauschdienst
- 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
- age-related macular degeneration, complement activation, retinal pigment epithelial cells, CD59, inflammatory cytokines, interleukin-6, interleukin-8, MCP-1, vascular endothelial growth factor, vitronectin, neovascular AMD, complement dysregulation
- MeSH terms
- Cell Line, Complement Activation, Humans, Immunohistochemistry, Macular Degeneration, Interleukin-6, Complement Membrane Attack Complex, Interleukin-8, Chemokine CCL2, Vitronectin, Matrix Metalloproteinases, Vascular Endothelial Growth Factor A, Retinal Pigment Epithelium
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