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Cited by 105Cholesterol and Lipid MetabolismAtherosclerosis and Cardiovascular DiseasesLipoproteins and Cardiovascular Health

Deletion of ABCA1 and ABCG1 Impairs Macrophage Migration Because of Increased Rac1 Signaling

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Pagler, Tamara A., Wang, Mi, Mondal, Mousumi, Murphy, Andrew J., Westerterp, Marit, Moore, Kathryn J., Maxfield, Frederick R., Tall, Alan R.·2011·Circulation Research
DOI 10.1161/circresaha.110.228619PMC PMC3097897
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Abstract

Rationale: Reduced plasma cholesterol and increased high-density lipoprotein (HDL) levels promote regression of atherosclerosis, in a process characterized by lipid unloading and emigration of macrophages from lesions. In contrast free cholesterol loading of macrophages leads to imbalanced Rac1/Rho activities and impaired chemotaxis. Objective: To study the role of HDL and the ATP-binding cassette transporters ABCA1 and ABCG1 in modulating the chemotaxis of macrophages. Methods and Results: Abca1 −/− Abcg1 −/− mouse macrophages displayed profoundly impaired chemotaxis both in a Transwell chamber assay and in the peritoneal cavity of wild-type (WT) mice. HDL reversed impaired chemotaxis in free cholesterol–loaded WT macrophages but was without effect in Abca1 −/− Abcg1 −/− cells, whereas cyclodextrin was effective in both. Abca1 −/− Abcg1 −/− macrophages had markedly increased Rac1 activity and increased association of Rac1 with the plasma membrane (PM). Their defective chemotaxis was reversed by a Rac1 inhibitor. To gain a better understanding of the role of transporters in PM cholesterol movement, we measured transbilayer PM sterol distribution. In WT macrophages, the majority of cholesterol was located on the inner leaflet, whereas on upregulation of transporters by liver X receptor activation, PM sterol was shifted to the outer leaflet, where it could be removed by HDL. Abca1 −/− Abcg1 −/− macrophages showed increased PM sterol content and defective redistribution of sterol to the outer leaflet. Conclusions: Deletion of ABCA1 and ABCG1 causes an increased cholesterol content on the inner leaflet of the PM, associated with increased Rac1 PM localization, activation, and impairment of migration. ABCA1 and ABCG1 facilitate macrophage chemotaxis by promoting PM transbilayer cholesterol movement and may contribute to the ability of HDL to promote regression of atherosclerosis.

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  • Previous work found that double knockout of ABCA1 and ABCG1 in macrophages resulted in decreased migratory capacity when stimulated with C5a, ascribed to Rac1 activation.

    “Previous work found that double knockout of ABCA1 and ABCG1 in macrophages resulted in decreased migratory capacity when stimulated with C5a (compliment component 5a), compared to wildtype macrophages, ascribed to Rac1 activation (55).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [55]

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Authors
Pagler, T. A., Wang, M., Mondal, M., Murphy, A. J., Westerterp, M., Moore, K. J., Maxfield, F. R., & Tall, A. R.
Affiliations
Cornell University (US)
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2011-01-21
Volume
108
Issue
2
Pages
194-200
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.110.228619
PMC
PMC3097897
OpenAlex
W2141914439
Cited by
105
References
1
Citations by year
2026: 4 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 9 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 2 · 2017: 6 · 2016: 10 · 2015: 8 · 2014: 8 · 2013: 12 · 2012: 10
FWCI
9.12
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
  • PubMed Central (acceptedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Funders
  • National Institute on Aging (R01AG020255, AG20255)
  • National Heart, Lung, and Blood Institute (P01HL054591, R01HL093324, HL 54591)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R37DK027083, R01DK027083)
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
ABCA1, ABCG1, macrophage migration, chemotaxis, Rac1 signaling, high-density lipoprotein, free cholesterol, liver X receptor, atherosclerosis regression, cyclodextrins
MeSH terms
ATP Binding Cassette Transporter, Subfamily G, Member 1, Actins, Animals, Cell Membrane, Cell Movement, Cells, Cultured, Chemotaxis, Cholesterol, Guanosine Triphosphate, Lipoproteins, Macrophages, Neuropeptides, Signal Transduction, Mice, Knockout, ATP-Binding Cassette Transporters, rac GTP-Binding Proteins, rac1 GTP-Binding Protein, Models, Animal, Mice, ATP Binding Cassette Transporter 1

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