This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 115/16/2168    most recent CIRCULATIONAHA.106.662080v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ait-Oufella, H. Articles by Mallat, Z. Search for Related Content PubMed PubMed Citation Articles by Ait-Oufella, H. Articles by Mallat, Z. Related Collections Apoptosis Pathophysiology Genetically altered mice Growth factors/cytokines Mechanism of atherosclerosis/growth factors

(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.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				D. J. GRAINGER When Worlds Collide: Autoimmunity and Atherosclerosis J Rheumatol, November 1, 2009; 36(11): 2378 - 2379. [Full Text] [PDF]

				E. Thorp and I. Tabas Mechanisms and consequences of efferocytosis in advanced atherosclerosis J. Leukoc. Biol., November 1, 2009; 86(5): 1089 - 1095. [Abstract] [Full Text] [PDF]

				S. Taleb, M. Romain, B. Ramkhelawon, C. Uyttenhove, G. Pasterkamp, O. Herbin, B. Esposito, N. Perez, H. Yasukawa, J. Van Snick, et al. Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis J. Exp. Med., September 28, 2009; 206(10): 2067 - 2077. [Abstract] [Full Text] [PDF]

				G. D. Norata, P. Marchesi, V. K. Pulakazhi Venu, F. Pasqualini, A. Anselmo, F. Moalli, I. Pizzitola, C. Garlanda, A. Mantovani, and A. L. Catapano Deficiency of the Long Pentraxin PTX3 Promotes Vascular Inflammation and Atherosclerosis Circulation, August 25, 2009; 120(8): 699 - 708. [Abstract] [Full Text] [PDF]

				M. J. Lewis, T. H. Malik, M. R. Ehrenstein, J. J. Boyle, M. Botto, and D. O. Haskard Immunoglobulin M Is Required for Protection Against Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice Circulation, August 4, 2009; 120(5): 417 - 426. [Abstract] [Full Text] [PDF]

				M. Wigren, D. Bengtsson, P. Duner, K. Olofsson, H. Bjorkbacka, E. Bengtsson, G. N. Fredrikson, and J. Nilsson Atheroprotective Effects of Alum Are Associated With Capture of Oxidized LDL Antigens and Activation of Regulatory T Cells Circ. Res., June 19, 2009; 104(12): e62 - e70. [Abstract] [Full Text] [PDF]

				Z. Fu, M. Wang, M. Gucek, J. Zhang, J. Wu, L. Jiang, R. E. Monticone, B. Khazan, R. Telljohann, J. Mattison, et al. Milk Fat Globule Protein Epidermal Growth Factor-8: A Pivotal Relay Element Within the Angiotensin II and Monocyte Chemoattractant Protein-1 Signaling Cascade Mediating Vascular Smooth Muscle Cells Invasion Circ. Res., June 19, 2009; 104(12): 1337 - 1346. [Abstract] [Full Text] [PDF]

				Md. M. Aziz, S. Ishihara, Y. Mishima, N. Oshima, I. Moriyama, T. Yuki, Y. Kadowaki, M. A. K. Rumi, Y. Amano, and Y. Kinoshita MFG-E8 Attenuates Intestinal Inflammation in Murine Experimental Colitis by Modulating Osteopontin-Dependent {alpha}v{beta}3 Integrin Signaling J. Immunol., June 1, 2009; 182(11): 7222 - 7232. [Abstract] [Full Text] [PDF]

				E. L. Gautier, T. Huby, J. L. Witztum, B. Ouzilleau, E. R. Miller, F. Saint-Charles, P. Aucouturier, M. J. Chapman, and P. Lesnik Macrophage Apoptosis Exerts Divergent Effects on Atherogenesis as a Function of Lesion Stage Circulation, April 7, 2009; 119(13): 1795 - 1804. [Abstract] [Full Text] [PDF]

				Z. Mallat, S. Taleb, H. Ait-Oufella, and A. Tedgui The role of adaptive T cell immunity in atherosclerosis J. Lipid Res., April 1, 2009; 50(Supplement): S364 - S369. [Abstract] [Full Text] [PDF]

				M. C.H. Clarke and M. R. Bennett Cause or Consequence: What Does Macrophage Apoptosis Do in Atherosclerosis? Arterioscler Thromb Vasc Biol, February 1, 2009; 29(2): 153 - 155. [Full Text] [PDF]

				E. Thorp, D. Cui, D. M. Schrijvers, G. Kuriakose, and I. Tabas Mertk Receptor Mutation Reduces Efferocytosis Efficiency and Promotes Apoptotic Cell Accumulation and Plaque Necrosis in Atherosclerotic Lesions of Apoe-/- Mice Arterioscler Thromb Vasc Biol, August 1, 2008; 28(8): 1421 - 1428. [Abstract] [Full Text] [PDF]

				Z. Mallat and A. Tedgui HDL, PTX3, and Vascular Protection Arterioscler Thromb Vasc Biol, May 1, 2008; 28(5): 809 - 811. [Full Text] [PDF]

				C. Shao, V. A. Novakovic, J. F. Head, B. A. Seaton, and G. E. Gilbert Crystal Structure of Lactadherin C2 Domain at 1.7A Resolution with Mutational and Computational Analyses of Its Membrane-binding Motif J. Biol. Chem., March 14, 2008; 283(11): 7230 - 7241. [Abstract] [Full Text] [PDF]

				B. C. Berk Atheroprotective Signaling Mechanisms Activated by Steady Laminar Flow in Endothelial Cells Circulation, February 26, 2008; 117(8): 1082 - 1089. [Full Text] [PDF]