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Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1
Open accessAbstract
Macrophages clear millions of apoptotic cells daily and, during this process, take up large quantities of cholesterol. The membrane transporter ABCA1 is a key player in cholesterol efflux from macrophages and has been shown via human genetic studies to provide protection against cardiovascular disease. How the apoptotic cell clearance process is linked to macrophage ABCA1 expression is not known. Here, we identified a plasma membrane-initiated signaling pathway that drives a rapid upregulation of ABCA1 mRNA and protein. This pathway involves the phagocytic receptor brain-specific angiogenesis inhibitor 1 (BAI1), which recognizes phosphatidylserine on apoptotic cells, and the intracellular signaling intermediates engulfment cell motility 1 (ELMO1) and Rac1, as ABCA1 induction was attenuated in primary macrophages from mice lacking these molecules. Moreover, this apoptotic cell-initiated pathway functioned independently of the liver X receptor (LXR) sterol-sensing machinery that is known to regulate ABCA1 expression and cholesterol efflux. When placed on a high-fat diet, mice lacking BAI1 had increased numbers of apoptotic cells in their aortic roots, which correlated with altered lipid profiles. In contrast, macrophages from engineered mice with transgenic BAI1 overexpression showed greater ABCA1 induction in response to apoptotic cells compared with those from control animals. Collectively, these data identify a membrane-initiated pathway that is triggered by apoptotic cells to enhance ABCA1 within engulfing phagocytes and with functional consequences in vivo.
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“Interestingly, apoptotic cells increase ABCA1, which is required for the secretion of ‘find me’ signals (65, 66).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [65]
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Metadata
- Authors
- Fond, A. M., Lee, C. S., Schulman, I. G., Kiss, R. S., & Ravichandran, K. S.
- Affiliations
- University of Virginia (US)
- McGill University Health Centre (CA)
- Corresponding author
- Fond, Aaron M.
- Lee, Chang Sup
- Ravichandran, Kodi S.
- Venue
- Journal of Clinical Investigation
- Published
- 2015-06-15
- Volume
- 125
- Issue
- 7
- Pages
- 2748-2758
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4563683
- OpenAlex
- W1754447511
- Cited by
- 114
- References
- 58
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 12 · 2023: 16 · 2022: 4 · 2021: 10 · 2020: 8 · 2019: 9 · 2018: 11 · 2017: 12 · 2016: 13 · 2015: 2
- FWCI
- 12.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL120840, P01HL120840)
- National Cancer Institute (P30CA044579)
- National Institute of General Medical Sciences (GM-064709, R01GM064709, T32GM007267)
- National Institute of Allergy and Infectious Diseases (T32AI007496)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- ABCA1, efferocytosis, macrophages, BAI1, ELMO1, Rac1, phosphatidylserine, membrane-initiated signaling, cholesterol efflux, liver X receptor, aortic root, high-fat diet, cardiovascular disease, atherosclerosis
- MeSH terms
- Liver X Receptors, Animals, Cell Membrane, Cholesterol, Female, Humans, Macrophages, Mice, Inbred C57BL, Mice, Transgenic, Neuropeptides, RNA, Messenger, Signal Transduction, Up-Regulation, Apoptosis, Mice, Knockout, Jurkat Cells, rac1 GTP-Binding Protein, Angiogenic Proteins, Adaptor Proteins, Signal Transducing, Lipid Metabolism, Mice, Orphan Nuclear Receptors, ATP Binding Cassette Transporter 1
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