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Lactadherin Deficiency Leads to Apoptotic Cell Accumulation and Accelerated Atherosclerosis in Mice
Abstract
Background— Atherosclerosis is an immunoinflammatory disease; however, the key factors responsible for the maintenance of immune regulation in a proinflammatory milieu are poorly understood. Methods and Results— Here, we show that milk fat globule-EGF factor 8 (Mfge8, also known as lactadherin) is expressed in normal and atherosclerotic human arteries and is involved in phagocytic clearance of apoptotic cells by peritoneal macrophages. Disruption of bone marrow–derived Mfge8 in a murine model of atherosclerosis leads to substantial accumulation of apoptotic debris both systemically and within the developing lipid lesions. The accumulation of apoptotic material is associated with a reduction in interleukin-10 in the spleen but an increase in interferon-γ production in both the spleen and the atherosclerotic arteries. In addition, we report a dendritic cell-dependent alteration of natural regulatory T-cell function in the absence of Mfge8. These events are associated with a marked acceleration of atherosclerosis. Conclusions— Lack of Mfge8 in bone marrow–derived cells enhances the accumulation of apoptotic cell corpses in atherosclerosis and alters the protective immune response, which leads to an acceleration of plaque development.
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“defective efferocytosis of apoptotic cells leading to secondary necrosis and leakage of intracellular contents has been proposed to exacerbate the inflammatory milieu 131,132,137 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [132]
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Metadata
- Authors
- Ait-Oufella, H., Kinugawa, K., Zoll, J., Simon, T., Boddaert, J., Heeneman, S., Blanc-Brude, O., Barateau, V., Potteaux, S., Merval, R., Esposito, B., Teissier, E., Daemen, M. J., Lesèche, G., Boulanger, C., Tedgui, A., & Mallat, Z.
- Affiliations
- From Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 689, Centre de Recherche Cardiovasculaire Lariboisière, Paris, France (H.A-O., K.K., J.Z., T.S., J.B., O.B-B., V.B., S.P., R.M., B.E., G.L., C.B., A.T., Z.M.); Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands (S.H., M.J.D.); INSERM U545, Institut Pasteur de Lille and Faculte de Pharmacie, Universite de Lille II, Lille, France (E.T.); and Service de Chirurgie Thoracique...
- Inserm (FR)
- ORCID
- Venue
- Circulation
- Published
- 2007-04-24
- Volume
- 115
- Issue
- 16
- Pages
- 2168-2177
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2139975300
- Cited by
- 255
- References
- 45
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 9 · 2023: 6 · 2022: 15 · 2021: 11 · 2020: 11 · 2019: 12 · 2018: 13 · 2017: 17 · 2016: 8 · 2015: 14 · 2014: 25 · 2013: 12 · 2012: 20
- FWCI
- 6.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Institut Gustave-Roussy
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- lactadherin, MFG-E8, atherosclerosis, efferocytosis, phagocytosis, peritoneal macrophages, bone marrow-derived cells, dendritic cells, regulatory T cells, IL-10, interferon-gamma, immune regulation, plaque development
- MeSH terms
- Animals, Antigens, Surface, Carotid Arteries, Coronary Artery Disease, Coronary Vessels, Diet, Atherogenic, Endothelium, Vascular, Humans, Interferon-gamma, Male, Milk Proteins, Muscle, Smooth, Vascular, Phagocytosis, Radiation Chimera, Bone Marrow Transplantation, Interleukin-10, Carotid Stenosis, Apoptosis, Macrophages, Peritoneal, Mice, Knockout, Disease Progression, Endothelial Cells, Atherosclerosis, T-Lymphocytes, Regulatory, Mice
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