RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium
BACKGROUND: Circulating platelets and chemoattractant proteins, such as the CC chemokine RANTES, contribute to the activation and interaction of monocytes and endothelium and may thereby play a pivotal role in the pathogenesis of inflammatory and atherosclerotic disease. METHODS AND RESULTS: The binding of RANTES to human endothelial cells was detected by ELISA or immunofluorescence after perfusion with platelets or exposure to their supernatants. Monocyte arrest on endothelial monolayers or surface-adherent platelets was studied with a parallel-wall flow chamber and video microscopy. We show that RANTES secreted by thrombin-stimulated platelets is immobilized on the surface of inflamed microvascular or aortic endothelium and triggers shear-resistant monocyte arrest under flow conditions, as shown by inhibition with the RANTES receptor antagonist Met-RANTES or a blocking RANTES antibody. Deposition of RANTES and its effects requires endothelial activation, eg, by interleukin-1beta, and is not supported by venous endothelium or adherent platelets. Immunohistochemistry revealed that RANTES is present on the luminal surface of carotid arteries of apolipoprotein E-deficient mice with early atherosclerotic lesions after wire-induced injury or cytokine exposure. In a mechanistic model of atherogenesis, monocyte adherence on endothelium covering such lesions was studied in murine carotid arteries perfused ex vivo, showing that the accumulation of monocytic cells in these carotid arteries involved RANTES receptors. CONCLUSIONS: The deposition of RANTES by platelets triggers shear-resistant monocyte arrest on inflamed or atherosclerotic endothelium. Delivery of RANTES by platelets may epitomize a novel principle relevant to inflammatory or atherogenic monocyte recruitment from the circulation.
|Authors:||von Hundelshausen P, Weber KS, Huo Y, Proudfoot AE, Nelson PJ, Ley K, Weber C|
|Journal:||Circulation 103: 1772-1777|
|PubMed:||Find in PubMed|