Chemokine fractalkine mediates leukocyte recruitment to inflammatory endothelial cells in flowing whole blood: A critical role for P-selectin expressed on activated platelets

Christian Schulz, Andreas Schäfer, Moritz Stolla, Sandra Kerstan, Michael Lorenz, Marie Luise Von Brühl, Matthias Schiemann, Johann Bauersachs, Torsten Gloe, Dirk H. Busch, Meinrad Gawaz, Steffen Massberg

Research output: Contribution to journalArticlepeer-review

142 Scopus citations

Abstract

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-α and interferon-γ 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.

Original languageEnglish
Pages (from-to)764-773
Number of pages10
JournalCirculation
Volume116
Issue number7
DOIs
StatePublished - Aug 2007

Keywords

  • Atherosclerosis
  • Endothelium
  • Inflammation
  • Leukocytes
  • Platelets

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