Cited by 391Atherosclerosis and Cardiovascular DiseasesCholesterol and Lipid MetabolismPhagocytosis and Immune Regulation

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Human Atherosclerotic Plaque Alternative Macrophages Display Low Cholesterol Handling but High Phagocytosis Because of Distinct Activities of the PPARγ and LXRα Pathways

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Chinetti-Gbaguidi, Giulia, Baron, Morgane, Bouhlel, Mohamed Amine, Vanhoutte, Jonathan, Copin, Corinne, Sebti, Yasmine, Derudas, Bruno, Mayi, Thérèse, Bories, Gael, Tailleux, Anne, Haulon, Stephane, Zawadzki, Christophe, Jude, Brigitte, Staels, Bart·2011·Circulation Research

DOI 10.1161/circresaha.110.233775PMC PMC3319502

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Abstract

Rationale: A crucial step in atherogenesis is the infiltration of the subendothelial space of large arteries by monocytes where they differentiate into macrophages and transform into lipid-loaded foam cells. Macrophages are heterogeneous cells that adapt their response to environmental cytokines. Th1 cytokines promote monocyte differentiation into M1 macrophages, whereas Th2 cytokines trigger an “alternative” M2 phenotype. Objective: We previously reported the presence of CD68 + mannose receptor (MR) + M2 macrophages in human atherosclerotic plaques. However, the function of these plaque CD68 + MR + macrophages is still unknown. Methods and Results: Histological analysis revealed that CD68 + MR + macrophages locate far from the lipid core of the plaque and contain smaller lipid droplets compared to CD68 + MR − macrophages. Interleukin (IL)-4–polarized CD68 + MR + macrophages display a reduced capacity to handle and efflux cellular cholesterol because of low expression levels of the nuclear receptor liver x receptor (LXR)α and its target genes, ABCA1 and apolipoprotein E, attributable to the high 15-lipoxygenase activity in CD68 + MR + macrophages. By contrast, CD68 + MR + macrophages highly express opsonins and receptors involved in phagocytosis, resulting in high phagocytic activity. In M2 macrophages, peroxisome proliferator-activated receptor (PPAR)γ activation enhances the phagocytic but not the cholesterol trafficking pathways. Conclusions: These data identify a distinct macrophage subpopulation with a low susceptibility to become foam cells but high phagocytic activity resulting from different regulatory activities of the PPARγ-LXRα pathways.

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Authors: Chinetti-Gbaguidi, G., Baron, M., Bouhlel, M. A., Vanhoutte, J., Copin, C., Sebti, Y., Derudas, B., Mayi, T., Bories, G., Tailleux, A., Haulon, S., Zawadzki, C., Jude, B., & Staels, B.
Affiliations: From Univ Lille Nord de France (G.C.-G., M.B., M.A.B., J.V., C.C., Y.S., B.D., T.M., G.B., A.T., C.Z., B.J., B.S.), F-59000, Lille; Inserm (G.C.-G., M.B., M.A.B., J.V., C.C., Y.S., B.D., T.M., G.B., A.T., B.S.), U1011, F-59000, Lille; UDSL (G.C.-G., M.B., M.A.B., J.V., C.C., Y.S., B.D., T.M., G.B., A.T., C.Z., B.J., B.S.), F-59000, Lille, France; Institut Pasteur de Lille (G.C.-G., M.B., M.A.B., J.V., C.C., Y.S., B.D., T.M., G.B., A.T., B.S.), F-59019, Lille; and EA2693 and Centre Hospitalier...
Inserm (FR)
ORCID: Bouhlel, Mohamed Amine
Sebti, Yasmine
Derudas, Bruno
Bories, Gael
Tailleux, Anne
Zawadzki, Christophe
Staels, Bart
Venue: Circulation Research
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2011-04-15
Volume: 108
Issue: 8
Pages: 985-995
ISSN: 0009-7330 (ISSN-L)
1524-4571
DOI: 10.1161/circresaha.110.233775
PMC: PMC3319502
OpenAlex: W2129909114
Cited by: 387
References: 43
Citations by year: 2026: 14 · 2025: 19 · 2024: 25 · 2023: 22 · 2022: 34 · 2021: 17 · 2020: 21 · 2019: 30 · 2018: 26 · 2017: 30 · 2016: 21 · 2015: 28 · 2014: 25 · 2013: 29 · 2012: 31
FWCI: 14.18
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Circulation Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
HAL (submittedVersion, other-oa)
LillOA (Université de Lille (University Of Lille)) (submittedVersion, other-oa)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords: M2 macrophages, CD206, CD68, phagocytosis, cholesterol efflux, ABCA1, apolipoprotein E, liver X receptor alpha, PPARγ, 15-lipoxygenase, foam cells, macrophage heterogeneity, opsonins
MeSH terms: Liver X Receptors, Cell Differentiation, Cells, Cultured, Cholesterol, Humans, Leukocytes, Mononuclear, Macrophages, Phagocytosis, Genetic Predisposition to Disease, PPAR gamma, Orphan Nuclear Receptors, Plaque, Atherosclerotic

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Human Atherosclerotic Plaque Alternative Macrophages Display Low Cholesterol Handling but High Phagocytosis Because of Distinct Activities of the PPARγ and LXRα Pathways

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