Published online before print November 8, 2007, doi: 10.1161/CIRCRESAHA.107.160697
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© 2008 American Heart Association, Inc.
Molecular Medicine |
Protective Role of CXC Receptor 4/CXC Ligand 12 Unveils the Importance of Neutrophils in Atherosclerosis
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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