A local complement response by RPE causes early-stage macular degeneration
Open accessAbstract
Inherited and age-related macular degenerations (AMDs) are important causes of vision loss. An early hallmark of these disorders is the formation of sub-retinal pigment epithelium (RPE) basal deposits. A role for the complement system in MDs was suggested by genetic association studies, but direct functional connections between alterations in the complement system and the pathogenesis of MD remain to be defined. We used primary RPE cells from a mouse model of inherited MD due to a p.R345W mutation in EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) to investigate the role of the RPE in early MD pathogenesis. Efemp1(R345W) RPE cells recapitulate the basal deposit formation observed in vivo by producing sub-RPE deposits in vitro. The deposits share features with basal deposits, and their formation was mediated by EFEMP1(R345W) or complement component 3a (C3a), but not by complement component 5a (C5a). Increased activation of complement appears to occur in response to an abnormal extracellular matrix (ECM), generated by the mutant EFEMP1(R345W) protein and reduced ECM turnover due to inhibition of matrix metalloproteinase 2 by EFEMP1(R345W) and C3a. Increased production of C3a also stimulated the release of cytokines such as interleukin (IL)-6 and IL-1B, which appear to have a role in deposit formation, albeit downstream of C3a. These studies provide the first direct indication that complement components produced locally by the RPE are involved in the formation of basal deposits. Furthermore, these results suggest that C3a generated by RPE is a potential therapeutic target for the treatment of EFEMP1-associated MD as well as AMD.
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Complement proteins C3 and Factor B (FB) have been found to be essential for drusen formation in mouse models of inherited retinal degeneration.
“In fact, complement proteins C3 and Factor B (FB) have been found to be essential for drusen formation in mouse models of inherited retinal degeneration [119,120,121].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [119]
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Widening the Spectrum of Disease Expression due to Heterozygous Variants in EFEMP1
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- Authors
- Fernandez-Godino, R., Garland, D. L., & Pierce, E. A.
- Affiliations
- Massachusetts Eye and Ear Infirmary (US)
- Corresponding author
- Pierce, Eric A.
- ORCID
- Pierce, Eric A.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-07-21
- Volume
- 24
- Issue
- 19
- Pages
- 5555-5569
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4572070
- OpenAlex
- W2141588316
- Cited by
- 73
- References
- 90
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 14 · 2020: 10 · 2019: 7 · 2018: 7 · 2017: 9 · 2016: 3
- FWCI
- 6.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- the Ocular Genomics Institute
- National Eye Institute Core (P30EY003790)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- age-related macular degeneration, retinal pigment epithelium, complement system, C3a, EFEMP1, extracellular matrix, MMP-2, interleukin-6, IL-1β, complement activation, therapeutic target
- MeSH terms
- Animals, Cells, Cultured, Disease Models, Animal, Extracellular Matrix, Macular Degeneration, Mutation, Complement C3a, Complement C5a, Extracellular Matrix Proteins, Matrix Metalloproteinases, Mice, Retinal Pigment Epithelium
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