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(Circulation. 2009;119:2367-2375.)
© 2009 American Heart Association, Inc.

Vascular Medicine

Conventional Dendritic Cells at the Crossroads Between Immunity and Cholesterol Homeostasis in Atherosclerosis

Emmanuel L. Gautier, PhD; Thierry Huby, PhD; Flora Saint-Charles, MSc; Betty Ouzilleau, BS; John Pirault, MSc; Virginie Deswaerte, MSc; Florent Ginhoux, PhD; Elizabeth R. Miller, BS; Joseph L. Witztum, MD; M. John Chapman, PhD, DSc; Philippe Lesnik, PhD

From INSERM UMR-S 939, Hôpital de la Pitié (E.L.G., T.H., F.S.-C., B.O., J.P., V.D., M.J.C., P.L.), Paris, France; Université Pierre et Marie Curie, Université Paris 06, UMR-S 939 (E.L.G., T.H., F.S.-C., B.O., J.P., V.D., M.J.C., P.L.), Paris, France; Assistance Publique–Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Service d’Endocrinologie-Métabolisme (T.H., M.J.C., P.L.), Paris, France; Department of Medicine, University of California San Diego (E.R.M., J.L.W.), La Jolla, Calif; and Department of Gene and Cell Medicine and Department of Medicine, Mount Sinai School of Medicine (F.G.), New York, NY.

Correspondence to Dr Philippe Lesnik, INSERM U939, Hôpital de la Pitié, 83 Bd de l’hôpital, 75651 Paris 13, France. E-mail philippe.lesnik{at}upmc.fr

Received July 15, 2008; accepted March 6, 2009.

Background— Immunoinflammatory mechanisms are implicated in the atherogenic process. The polarization of the immune response and the nature of the immune cells involved, however, are major determinants of the net effect, which may be either proatherogenic or antiatherogenic. Dendritic cells (DCs) are central to the regulation of immunity, the polarization of the immune response, and the induction of tolerance to antigens. The potential role of DCs in atherosclerosis, however, remains to be defined.

Methods and Results— We created a mouse model in which the lifespan and immunogenicity of conventional DCs are enhanced by specific overexpression of the antiapoptotic gene hBcl-2 under the control of the CD11c promoter. When studied in either low-density lipoprotein receptor–deficient or apolipoprotein E–deficient backgrounds, DC-hBcl2 mice exhibited an expanded DC population associated with enhanced T-cell activation, a T-helper 1 and T-helper 17 cytokine expression profile, and elevated production of T-helper 1–driven IgG2c autoantibodies directed against oxidation-specific epitopes. This proatherogenic signature, however, was not associated with acceleration of atherosclerotic plaque progression, because expansion of the DC population was unexpectedly associated with an atheroprotective decrease in plasma cholesterol levels. Conversely, depletion of DCs in hyperlipidemic CD11c–diphtheria toxin receptor/apolipoprotein E–deficient transgenic mice resulted in enhanced cholesterolemia, thereby arguing for a close relationship between the DC population and plasma cholesterol levels.

Conclusions— Considered together, the present data reveal that conventional DCs are central to the atherosclerotic process, because they are directly implicated in both cholesterol homeostasis and the immune response.

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