Impaired Cholesterol Efflux in Senescent Macrophages Promotes Age-Related Macular Degeneration
Open accessAbstract
Pathologic angiogenesis mediated by abnormally polarized macrophages plays a central role in common age-associated diseases such as atherosclerosis, cancer, and macular degeneration. Here we demonstrate that abnormal polarization in older macrophages is caused by programmatic changes that lead to reduced expression of ATP binding cassette transporter ABCA1. Downregulation of ABCA1 by microRNA-33 impairs the ability of macrophages to effectively efflux intracellular cholesterol, which in turn leads to higher levels of free cholesterol within senescent macrophages. Elevated intracellular lipid polarizes older macrophages to an abnormal, alternatively activated phenotype that promotes pathologic vascular proliferation. Mice deficient for Abca1, but not Abcg1, demonstrate an accelerated aging phenotype, whereas restoration of cholesterol efflux using LXR agonists or miR-33 inhibitors reverses it. Monocytes from older humans with age-related macular degeneration showed similar changes. These findings provide an avenue for therapeutic modulation of macrophage function in common age-related diseases.
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HMVECs cocultured with BMDMs from myeloid cell conditional ABCA1 knockout mice had increased proliferation.
“Similar to our findings, HMVECs cocultured with BMDMs from myeloid cell conditional ABCA1 knockout mice had increased proliferation (59).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [59]
The Results section reports that HMVECs cocultured with macrophages from myeloid-conditional Abca1 knockout mice showed greater proliferation than those cocultured with wild-type macrophages. However, the Vascular Endothelial Cell Proliferation Assay specifies peritoneal macrophages, not bone-marrow-derived macrophages (BMDMs). (LLM, conf=0.90)
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References 45 · Cited by 277
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- Authors
- Sene, A., Khan, A. A., Cox, D., Nakamura, R. E. I., Santeford, A., Kim, B. M., Sidhu, R., Onken, M. D., Harbour, J. W., Hagbi-Levi, S., Chowers, I., Edwards, P. A., Baldan, A., Parks, J. S., Ory, D. S., & Apte, R. S.
- Affiliations
- Washington University in St. Louis (US)
- Hadassah Medical Center (IL)
- University of California, Los Angeles (US)
- Wake Forest University Health Sciences (US)
- Corresponding author
- Apte, Rajendra S.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 17
- Issue
- 4
- Pages
- 549-561
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3640261
- OpenAlex
- W2050546552
- Cited by
- 277
- References
- 45
- Citations by year
- 2026: 19 · 2025: 19 · 2024: 24 · 2023: 23 · 2022: 22 · 2021: 24 · 2020: 17 · 2019: 18 · 2018: 28 · 2017: 22 · 2016: 19 · 2015: 8 · 2014: 20 · 2013: 11 · 2012: 1
- FWCI
- 19.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p60dk020579-35)
- National Heart, Lung, and Blood Institute (HL3 0568, P01HL030568, R01HL094525, R01HL067773, HL107794, R01HL107794, P01HL049373)
- National Eye Institute (R01EY019287, P30EY002687, K08EY016139, P30 EY-02687)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60-DK-020579, P30DK020579)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- age-related macular degeneration, macrophage senescence, cholesterol efflux, ABCA1, microRNA-33, free cholesterol, macrophage polarization, alternative activation, pathological angiogenesis, LXR agonists, aging, monocytes
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 1, Animals, Cells, Cultured, Cholesterol, Endothelium, Vascular, Humans, Leukocytes, Mononuclear, Lipoproteins, Macrophages, Macular Degeneration, Mice, Inbred C57BL, Mice, Obese, Neovascularization, Pathologic, Phenotype, Cellular Senescence, Mice, Knockout, ATP-Binding Cassette Transporters, MicroRNAs, Cell Proliferation, Mice, Diet, High-Fat, ATP Binding Cassette Transporter 1
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