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(Circulation. 2007;115:2168-2177.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Lactadherin Deficiency Leads to Apoptotic Cell Accumulation and Accelerated Atherosclerosis in Mice

Hafid Ait-Oufella, MD; Kiyoka Kinugawa, MD; Joffrey Zoll, PhD; Tabassome Simon, MD, PhD; Jacques Boddaert, MD, PhD; Silvia Heeneman, PhD; Olivier Blanc-Brude, PhD; Véronique Barateau; Stéphane Potteaux, PhD; Régine Merval; Bruno Esposito; Elisabeth Teissier, PhD; Mat J. Daemen, MD, PhD; Guy Lesèche, MD, PhD; Chantal Boulanger, PhD; Alain Tedgui, PhD; Ziad Mallat, MD, PhD

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 et Vasculaire, Hôpital Bichat, Paris, France (G.L.).

Correspondence to Ziad Mallat, MD, PhD, Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 689, Centre de Recherche Cardiovasculaire Lariboisière, 41 Bd de la Chapelle, 75010, Paris, France. E-mail mallat{at}larib.inserm.fr

Received August 30, 2006; accepted February 16, 2007.

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- 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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