Published online before print August 6, 2007, doi: 10.1161/CIRCULATIONAHA.107.695189
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(Circulation. 2007;116:764-773.)
© 2007 American Heart Association, Inc.
Vascular Medicine |
Chemokine Fractalkine Mediates Leukocyte Recruitment to Inflammatory Endothelial Cells in Flowing Whole Blood
A Critical Role for P-Selectin Expressed on Activated Platelets
From the Deutsches Herzzentrum München (C.S., M. Stolla, S.K., M.L., M.-L.v.B., S.M.), Institut für Medizinische Mikrobiologie, Immunologie und Hygiene (M. Schiemann, D.H.B.), Klinische Kooperationsgruppe ‘Antigen-spezifische Immuntherapie’ (M. Schiemann, D.H.B.), GSF-Forschungszentrum für Umwelt und Gesundheit, Technische Universität, München, Germany; the Medizinische Klinik und Poliklinik I (A.S., J.B.), Universitätsklinikum, Julius-Maximilians-Universität Würzburg, Germany; the Institut für Physiologie (T.G.), Ludwig-Maximilians Universität München, Germany; and the Medizinische Klinik III (M.G.), Eberhard-Karls-Universität Tübingen, Germany. Dr Massberg is currently affiliated with CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, Mass.
Correspondence to Dr Christian Schulz, Deutsches Herzzentrum, Lazarettstrasse 36, 80636 Munich, Germany. E-mail schulz{at}dhm.mhn.de
Received April 30, 2006; accepted May 29, 2007.
Background— The membrane-bound chemokine fractalkine (CX3CL1) is expressed on various cell types such as activated endothelial cells and has been implicated in the inflammatory process of atherosclerosis. The aim of the present study was to dissect the role of fractalkine in leukocyte recruitment to inflamed endothelium under arterial shear forces.
Methods and Results— With the use of immunofluorescence and laminar flow assays, the present study shows that human umbilical vein endothelial cells stimulated with tumor necrosis factor-
and interferon-
abundantly express CX3CL1 and promote substantial leukocyte accumulation under arterial flow conditions. In the presence of high shear, firm adhesion of leukocytes to inflamed endothelial cells is reduced by 
40% by a function-blocking anti-fractalkine antibody or by an antibody directed against the fractalkine receptor (CX3CR1). With the use of intravital video-fluorescence microscopy we demonstrate that inhibition of fractalkine signaling attenuates leukocyte adhesion to the atherosclerotic carotid artery of apolipoprotein E–deficient mice, which suggests that the CX3CL1-CX3CR1 axis is critically involved in leukocyte adhesion to inflamed endothelial cells under high shear forces both in vitro and in vivo. Surprisingly, platelets were strictly required for fractalkine-induced leukocyte adhesion at high shear rates. Correspondingly, specific inhibition of platelet adhesion to inflamed endothelial cells also significantly reduced leukocyte accumulation. We show that both soluble and membrane-bound fractalkine induces platelet degranulation and subsequent surface expression of P-selectin, which thereby promotes direct platelet-leukocyte interaction.
Conclusion— Fractalkine expressed by inflamed endothelial cells triggers P-selectin exposure on adherent platelets, which thereby initiates the local accumulation of leukocytes under arterial shear, an essential step in the development of atherosclerotic lesions.