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(Circulation Research. 2008;102:209.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Protective Role of CXC Receptor 4/CXC Ligand 12 Unveils the Importance of Neutrophils in Atherosclerosis

Alma Zernecke, Ilze Bot, Yassin Djalali-Talab, Erdenechimeg Shagdarsuren, Kiril Bidzhekov, Svenja Meiler, Regina Krohn, Andreas Schober, Markus Sperandio, Oliver Soehnlein, Jörg Bornemann, Frank Tacke, Erik A. Biessen, Christian Weber

From the Institute for Molecular Cardiovascular Research (A.Z., Y.D.-T., E.S., K.B., S.M., R.K., C.W.), Institute of Pathology (J.B.), and Medical Clinic III (F.T.), Rheinisch-Westfälische Technische Hochschule, Aachen University, Germany; Division of Biopharmaceutics (I.B., E.A.B.), Gorlaeus Laboratories, Leiden University, The Netherlands; Medical Policlinic (A.S.) and Institute of Physiology (M.S.), Ludwig-Maximilians-University, Munich, Germany; and Department of Physiology (O.S.), Karolinska Institute, Stockholm, Sweden.

Correspondence to Dr Christian Weber, Institut für Kardiovaskuläre Molekularbiologie, Universitätsklinikum Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany. E-mail cweber{at}ukaachen.de

The CXC ligand (CXCL)12/CXC receptor (CXCR)4 chemokine–receptor axis controls hematopoiesis, organ development, and angiogenesis, but its role in the inflammatory pathogenesis of atherosclerosis is unknown. Here we show that interference with Cxcl12/Cxcr4 by a small-molecule antagonist, genetic Cxcr4 deficiency, or lentiviral transduction with Cxcr4 degrakine in bone marrow chimeras aggravated diet-induced atherosclerosis in apolipoprotein E-deficient (Apoe^–/–) or LDL receptor–deficient (Ldlr^–/–) mice. Chronic blockade of Cxcr4 caused leukocytosis and an expansion of neutrophils and increased neutrophil content in plaques, associated with apoptosis and a proinflammatory phenotype. Whereas circulating neutrophils were recruited to atherosclerotic lesions, depletion of neutrophils reduced plaque formation and prevented its exacerbation after blocking Cxcr4. Disrupting Cxcl12/Cxcr4 thus promotes lesion formation through deranged neutrophil homeostasis, indicating that Cxcl12/Cxcr4 controls the important contribution of neutrophils to atherogenesis in mice

Key Words: atherosclerosis • cardiovascular disease • chemokines • leukocytes • vascular inflammation

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