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Circulation. 2007 Apr 24;115(16):2168-77. Epub 2007 Apr 9.

Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice.

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  • 1Institut National de la Santé et de la Recherche Médicale, Unit 689, Centre de Recherche Cardiovasculaire Lariboisière, 41 Bd de la Chapelle, 75010, Paris, France.

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-gamma 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.

PMID:
17420351
[PubMed - indexed for MEDLINE]
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