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Published on: February 10, 2021
A2E accumulation influences retinal microglial activation and complement regulation
Wenxin Ma1, Steven Coon, Lian Zhao
1Unit on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
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.
Insights
Accumulation of A2E, a lipofuscin component, activates retinal microglia and impairs their protective functions. This suggests a mechanism for immune dysregulation in age-related macular degeneration.
Area of Science:
- Ophthalmology
- Immunology
- Cell Biology
Background:
- Age-related macular degeneration (AMD) is an outer retinal disease linked to aging and immune dysfunction.
- In aging retinas, microglia accumulate lipofuscin deposits, potentially altering their function.
- A2E is a primary bisretinoid component of ocular lipofuscin.
Purpose of the Study:
- To investigate if A2E accumulation affects retinal microglia physiology in ways relevant to AMD.
- To understand the cellular mechanisms underlying microglial dysfunction in AMD pathogenesis.
Main Methods:
- Cultured retinal microglia were exposed to sublethal A2E accumulations.
- Microglial activation, neuroprotection, chemokine receptor expression, chemotaxis, and complement regulation were assessed.
Main Results:
- Sublethal A2E accumulation increased microglial activation and reduced neuroprotection of photoreceptors.
- A2E decreased microglial chemokine receptor expression and suppressed chemotaxis.
- A2E altered complement regulation, increasing complement factor B and decreasing complement factor H, promoting complement activation.
Conclusions:
- Ocular lipofuscin accumulation in microglia contributes to outer retinal immune dysregulation in AMD.
- Microglia play a key role in regulating local complement activation in the retina.
- Age-related lipofuscin buildup in microglia is a potential cellular mechanism driving AMD pathogenesis.
