Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice.
BACKGROUND
Atherosclerosis is an immunoinflammatory disease; however, the key factors responsible for the maintenance of immune regulation in a proinflammatory milieu are poorly understood.


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.
Ait-Oufella
Hafid
H
Institut National de la Santé et de la Recherche Médicale, Unit 689, Centre de Recherche Cardiovasculaire Lariboisière, 41 Bd de la Chapelle, 75010, Paris, France.
Kinugawa
Kiyoka
K
Zoll
Joffrey
J
Simon
Tabassome
T
Boddaert
Jacques
J
Heeneman
Silvia
S
Blanc-Brude
Olivier
O
Barateau
Véronique
V
Potteaux
Stéphane
S
Merval
Régine
R
Esposito
Bruno
B
Teissier
Elisabeth
E
Daemen
Mat J
MJ
Lesèche
Guy
G
Boulanger
Chantal
C
Tedgui
Alain
A
Mallat
Ziad
Z
D000818:Animals; D000954:Antigens, Surface / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D016026:Bone Marrow Transplantation; D002339:Carotid Arteries / Q000737:chemistry; D016893:Carotid Stenosis / Q000378:metabolism* / Q000473:pathology; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000737:chemistry; D004036:Diet, Atherogenic; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008894:Milk Proteins / Q000032:analysis / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis / Q000502:physiology; D011828:Radiation Chimera; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D000954:Antigens, Surface; C098942:MFGE8 protein, human; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D016753:Interleukin-10; D007371:Interferon-gamma