Published Online
on April 9, 2007

A more recent version of this article appeared on April 24, 2007

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Submitted on August 30, 2006
Accepted on February 16, 2007

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, and 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.).

^* To whom correspondence should be addressed. E-mail: mallat{at}larib.inserm.fr.

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.

Key words: atherosclerosis • apoptosis • immune system • inflammation • interleukins

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