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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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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Engulfment of cellular debris relies on the availability of free fatty acids, which are released upon degradation of lipid droplets, linking effective lysis of lipid droplets with successful phagocytosis.
“In this context, a study in macrophages has shown that engulfment of cellular debris relies on the availability of free fatty acids, which are released upon degradation of lipid droplets, thus linking effective lysis of lipid droplets with successful phagocytosis47.”
From Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain (2020) · cites this paper as [47]
PPARs act as master regulators governing the polarization of macrophages and microglia into M2 or alternative activation states associated with suppression of inflammation and promotion of phagocytosis and tissue repair.
“It has recently been appreciated that PPARs act as master regulators governing the polarization of macrophages and microglia into “M2” or “alternative” activation states associated with the suppression of inflammation and promotion of phagocytosis and tissue repair (Chawla, 2010; Chinetti-Gbaguidi et al., 2011).”
From Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease (2012) · cites this paper as Chinetti-Gbaguidi et al., 2011
PPARγ activation enhances the phagocytic capabilities of peripheral M2 polarized macrophages.
“PPARγ activation has been shown to enhance the phagocytic capabilities of peripheral M2 polarized macrophages (Chinetti-Gbaguidi et al., 2011).”
From Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease (2012) · cites this paper as Chinetti-Gbaguidi et al., 2011
Modulating microglial activation status by targeting nuclear receptors appears to restore the competence of these cells to phagocytose and clear amyloid in the AD brain.
“Thus, modulating microglial activation status by targeting nuclear receptors appears to restore the competence of these cells to phagocytose and clear amyloid in the AD brain (Mukundan et al., 2009; Chinetti-Gbaguidi et al., 2011).”
From Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease (2012) · cites this paper as Chinetti-Gbaguidi et al., 2011
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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
- Venue
- Circulation Research
- Published
- 2011-04-15
- Volume
- 108
- Issue
- 8
- Pages
- 985-995
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- 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
- Health Sciences › Medicine › Surgery › 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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