A2E accumulation influences retinal microglial activation and complement regulation
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Age-related macular degeneration is an outer retinal disease that involves aging and immune dysfunction. In the aging retina, microglia aggregate in the outer retina and acquire intracellular autofluorescent lipofuscin deposits. In this study, we investigated whether accumulation of A2E, a key bisretinoid constituent of ocular lipofuscin, alters the physiology of retinal microglia in pathologically relevant ways. Our findings show that sublethal accumulations of intracellular A2E in cultured retinal microglia increased microglial activation and decreased microglial neuroprotection of photoreceptors. Increased A2E accumulation also lowered microglial expression of chemokine receptors and suppressed microglial chemotaxis, suggesting that lipofuscin accumulation may potentiate subretinal microglial accumulation. Significantly, A2E accumulation altered microglial complement regulation by increasing complement factor B and decreasing complement factor H expression, favoring increased complement activation and deposition in the outer retina. Taken together, our findings highlight the role of microglia in the local control of complement activation in the retina and present the age-related accumulation of ocular lipofuscin in subretinal microglia as a cellular mechanism capable of driving outer retinal immune dysregulation in age-related macular degeneration pathogenesis.
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Aged microglia tend to accumulate lipofuscin, which has been associated with dysfunction and inflammation.
“Aged microglia also tend to accumulate lipofuscin [52–54], aggregations of highly oxidized proteins cross-linked with sugars and lipids [55], which have been associated with dysfunction and inflammation [56,57].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [56]
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- Authors
- Ma, W., Coon, S., Zhao, L., Fariss, R. N., & Wong, W. T.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Wong, Wai T.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 34
- Issue
- 3
- Pages
- 943-960
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC3480997
- OpenAlex
- W2063005088
- Cited by
- 92
- References
- 87
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 9 · 2020: 5 · 2019: 8 · 2018: 8 · 2017: 4 · 2016: 10 · 2015: 12 · 2014: 12 · 2013: 9 · 2012: 2
- FWCI
- 10.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Health Assistance Foundation
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- A2E, bisretinoids, lipofuscin, retinal microglia, microglial activation, age-related macular degeneration, complement regulation, factor B, complement factor H, complement activation, chemokine receptors, microglial chemotaxis, outer retina, retinal aging, immune dysregulation
- MeSH terms
- CX3C Chemokine Receptor 1, Aged, Aged, 80 and over, Aging, Animals, Cell Migration Inhibition, Cells, Cultured, Complement Activation, Humans, Lipofuscin, Macular Degeneration, Mice, Transgenic, Middle Aged, Complement Factor B, Pyridinium Compounds, Retina, Retinoids, Complement Factor H, Microglia, Receptors, Chemokine, Mice
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