Complement system dysregulation and inflammation in the retinal pigment epithelium of a mouse model for stargardt macular degeneration
Open accessAbstract
Accumulation of vitamin A-derived lipofuscin fluorophores in the retinal pigment epithelium (RPE) is a pathologic feature of recessive Stargardt macular dystrophy, a blinding disease caused by dysfunction or loss of the ABCA4 transporter in rods and cones. Age-related macular degeneration, a prevalent blinding disease of the elderly, is strongly associated with mutations in the genes for complement regulatory proteins (CRP), causing chronic inflammation of the RPE. Here we explore the possible relationship between lipofuscin accumulation and complement activation in vivo. Using the abca4(-/-) mouse model for recessive Stargardt, we investigated the role of lipofuscin fluorophores (A2E-lipofuscin) on oxidative stress and complement activation. We observed higher expression of oxidative-stress genes and elevated products of lipid peroxidation in eyes from abca4(-/-) versus wild-type mice. We also observed higher levels of complement-activation products in abca4(-/-) RPE cells. Unexpectedly, expression of multiple CRPs, which protect cells from attack by the complement system, were lower in abca4(-/-) versus wild-type RPE. To test whether acute exposure of healthy RPE cells to A2E-lipofuscin affects oxidative stress and expression of CRPs, we fed cultured fetal-derived human RPE cells with rod outer segments from wild-type or abca4(-/-) retinas. In contrast to RPE cells in abca4(-/-) mice, human RPE cells exposed to abca4(-/-) rod outer segments adaptively increased expression of both oxidative-stress and CRP genes. These results suggest that A2E accumulation causes oxidative stress, complement activation, and down-regulation of protective CRP in the Stargardt mouse model. Thus, Stargardt disease and age-related macular degeneration may both be caused by chronic inflammation of the RPE.
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Human fetal RPE cultures carrying a complement factor H risk haplotype have increased susceptibility to oxidative stress and complement attack when fed OSs from Abca4−/− mice.
“Human fetal RPE cultures carrying a complement factor H risk haplotype were found to have an increased susceptibility to oxidative stress and complement attack when fed OSs from Abca4−/− mice (Radu et al., 2011, 2014)”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Radu et al., 2011
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References 51 · Cited by 157
Research works printed but not linked: 6
- Hageman, G. S., Anderson, D. H., Johnson, L. V., Hancox, L. S., Taiber, A. J., Hardisty, L. I., Hageman, J. L., Stockman, H. A., Borchardt, J. D., Gehrs, K. M., Smith, R. J., Silvestri, G., Russell, S. R., Klaver, C. C., Barba- zetto, I., Chang, S., Yannuzzi, L. A., Barile, G. R., Merriam, J. C., Smith, R. T., Olsh, A. K., Bergeron, J., Zernant, J., Merriam, J. E., Gold, B., Dean, M., and Allikmets, R. (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 7227-7232
- Radu, R. A., Mata, N. L., Bagla, A., and Travis, G. H. (2004) Proc. Natl. Acad. Sci. U.S.A. 101, 5928 -5933
- Zhou, J., Jang, Y. P., Kim, S. R., and Sparrow, J. R. (2006) Proc. Natl. Acad. Sci. U.S.A. 103, 16182-16187
- Parish, C. A., Hashimoto, M., Nakanishi, K., Dillon, J., and Sparrow, J. (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 14609 -14613
- Mata, N. L., Weng, J., and Travis, G. H. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 7154 -7159
- Johnson, P. T., Betts, K. E., Radeke, M. J., Hageman, G. S., Anderson, D. H., and Johnson, L. V. (2006) Proc. Natl. Acad. Sci. U.S.A. 103, 17456 -17461
- Authors
- Radu, R. A., Hu, J., Yuan, Q., Welch, D. L., Makshanoff, J., Lloyd, M., McMullen, S., Travis, G. H., & Bok, D.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Radu, Roxana A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 286
- Issue
- 21
- Pages
- 18593-18601
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3099675
- OpenAlex
- W2058378174
- Cited by
- 157
- References
- 51
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 8 · 2023: 7 · 2022: 11 · 2021: 10 · 2020: 16 · 2019: 8 · 2018: 19 · 2017: 8 · 2016: 3 · 2015: 11 · 2014: 12 · 2013: 10 · 2012: 16
- FWCI
- 12.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Health Assistance Foundation
- Foundation Fighting Blindness
- Macula Vision Research Foundation
- National Institutes of Health (EY 00331)
- National Eye Institute (EY-017404, EY-00331, R01EY011713, R24EY017404, P30EY000331)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- Stargardt disease, age-related macular degeneration, retinal pigment epithelium, lipofuscin accumulation, A2E, ABCA4, complement regulatory proteins, oxidative stress, lipid peroxidation, chronic inflammation, rod outer segments, mouse model
- MeSH terms
- Animals, Complement System Proteins, Complement Activation, Humans, Lipofuscin, Macular Degeneration, Mice, Inbred BALB C, Retinal Rod Photoreceptor Cells, Retinal Cone Photoreceptor Cells, Mice, Knockout, Oxidative Stress, ATP-Binding Cassette Transporters, Mice, Retinal Pigment Epithelium
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