7-Ketocholesterol increases retinal microglial migration, activation, and angiogenicity: a potential pathogenic mechanism underlying age-related macular degeneration.
Open accessAbstract
Age-related macular degeneration (AMD) has been associated with both accumulation of lipid and lipid oxidative products, as well as increased neuroinflammatory changes and microglial activation in the outer retina. However, the relationships between these factors are incompletely understood. 7-Ketocholesterol (7KCh) is a cholesterol oxidation product localized to the outer retina with prominent pro-inflammatory effects. To explore the potential relationship between 7KCh and microglial activation, we localized 7KCh and microglia to the outer retina of aged mice and investigated 7KCh effects on retinal microglia in both in vitro and in vivo systems. We found that retinal microglia demonstrated a prominent chemotropism to 7KCh and readily internalized 7KCh. Sublethal concentrations of 7KCh resulted in microglial activation and polarization to a pro-inflammatory M1 state via NLRP3 inflammasome activation. Microglia exposed to 7KCh reduced expression of neurotrophic growth factors but increased expression of angiogenic factors, transitioning to a more neurotoxic and pro-angiogenic phenotype. Finally, subretinal transplantation of 7KCh-exposed microglia promoted choroidal neovascularization (CNV) relative to control microglia in a Matrigel-CNV model. The interaction of retinal microglia with 7KCh in the aged retina may thus underlie how outer retinal lipid accumulation in intermediate AMD results in neuroinflammation that ultimately drives progression towards advanced AMD.
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Subretinal injection of 7KCh has been shown to induce migration of Iba1 positive microglia to the outer retina suggesting a role as a chemo-attractant and thus altering the immune environment.
“Subretinal injection of 7KCh has been shown to induce migration of Iba1 positive microglia to the outer retina suggesting a role as a chemo-attractant and thus altering the immune environment (Indaram et al., 2015).”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Indaram et al., 2015
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- Authors
- Indaram, M., Ma, W., Zhao, L., Fariss, R. N., Rodriguez, I. R., & Wong, W. T.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Wong, Wai T.
- Venue
- Scientific Reports
- Published
- 2015-03-16
- Volume
- 5
- Issue
- 1
- Pages
- 9144-9144
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4360733
- OpenAlex
- W1972548733
- Cited by
- 101
- References
- 81
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 7 · 2023: 10 · 2022: 12 · 2021: 10 · 2020: 9 · 2019: 6 · 2018: 8 · 2017: 5 · 2016: 15 · 2015: 3 · 2014: 1
- FWCI
- 9.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Keywords
- 7-ketocholesterol, age-related macular degeneration, retinal microglia, microglial activation, M1 macrophage polarization, NLRP3 inflammasome, neuroinflammation, choroidal neovascularization, angiogenic factors, neurotrophic factors, cholesterol oxidation, outer retina, microglial chemotaxis, intermediate AMD
- MeSH terms
- CX3C Chemokine Receptor 1, Animals, Cell Survival, Chemotactic Factors, Disease Models, Animal, Gene Expression Regulation, Ketocholesterols, Macular Degeneration, Mice, Transgenic, Neovascularization, Pathologic, Nerve Growth Factors, Retina, Microglia, Receptors, Chemokine, Cell Proliferation, Mice
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