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(Circulation. 2008;117:1649-1657.)
© 2008 American Heart Association, Inc.

Coronary Heart Disease

Combined Inhibition of CCL2, CX3CR1, and CCR5 Abrogates Ly6C^hi and Ly6C^lo Monocytosis and Almost Abolishes Atherosclerosis in Hypercholesterolemic Mice

Christophe Combadière, PhD^*; Stéphane Potteaux, PhD^*; Mathieu Rodero, MBSc; Tabassome Simon, MD, PhD; Adeline Pezard, MBSc; Bruno Esposito, BSc; Régine Merval, BSc; Amanda Proudfoot, PhD; Alain Tedgui, PhD; Ziad Mallat, MD, PhD

From the Institut National de la Santé et de la Recherche Médicale, Unit 543 (C.C., M.R., A. Pezard) and Unit 689 (S.P., T.S., B.E., R.M., AT., Z.M.), Université Pierre et Marie Curie, Paris 6 (C.C.), Paris, France; and Serono Pharmaceutical Research Institute, Geneva, Switzerland (A. Proudfoot).

Correspondence to Ziad Mallat, MD, PhD, Inserm U689, Centre de Recherche Cardiovasculaire Lariboisière, 41, Bd de la Chapelle, 75010 Paris, France. E-mail mallat{at}larib.inserm.fr

Received October 9, 2007; accepted February 1, 2008.

Background— Monocytes are critical mediators of atherogenesis. Deletion of individual chemokines or chemokine receptors leads to significant but only partial inhibition of lesion development, whereas deficiency in other signals such as CXCL16 or CCR1 accelerates atherosclerosis. Evidence that particular chemokine pathways may cooperate to promote monocyte accumulation into inflamed tissues, particularly atherosclerotic arteries, is still lacking.

Methods and Results— Here, we show that chemokine-mediated signals critically determine the frequency of monocytes in the blood and bone marrow under both noninflammatory and atherosclerotic conditions. Particularly, CCL2-, CX3CR1-, and CCR5-dependent signals differentially alter CD11b⁺ Ly6G^– 7/4^hi (also known as Ly6C^hi) and CD11b⁺ Ly6G^– 7/4^lo (Ly6C^lo) monocytosis. Combined inhibition of CCL2, CX3CR1, and CCR5 in hypercholesterolemic, atherosclerosis-susceptible apolipoprotein E–deficient mice leads to abrogation of bone marrow monocytosis and to additive reduction in circulating monocytes despite persistent hypercholesterolemia. These effects are associated with a marked and additive 90% reduction in atherosclerosis. Interestingly, lesion size highly correlates with the number of circulating monocytes, particularly the CD11b⁺ Ly6G^– 7/4^lo subset.

Conclusions— CCL2, CX3CR1, and CCR5 play independent and additive roles in atherogenesis. Signals mediated through these pathways critically determine the frequency of circulating monocyte subsets and thereby account for almost all macrophage accumulation into atherosclerotic arteries.

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