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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1375.)
© 2008 American Heart Association, Inc.

Cell Biology and Signaling

Complete Downmodulation of P-Selectin Glycoprotein Ligand in Monocytes Undergoing Apoptosis

Jan-Julius Stampfuss; Petra Censarek; Jens W. Fischer; Gernot Kaber; Bernhard H. Rauch; Kerstin Freidel; Ute Fischer; Klaus Schulze-Osthoff; Tilo Grosser; Maria Grandoch; Karsten Schrör; Artur-Aron Weber

From the Institut für Pharmakologie und Klinische Pharmakologie (J.-J.S., P.C., J.W.F., G.K., B.H.R., K.F., K.S.), Universitätsklinikum Düsseldorf, Germany; the Institut für Molekulare Medizin (U.T., K.S.-O.), Universitätsklinikum Düsseldorf, Germany; the Institute for Translational Medicine and Therapeutics (T.G.), University of Pennsylvania School of Medicine, Philadelphia; and the Institut für Pharmakologie (M.G., A.-A.W.), Universität Duisburg-Essen, Universitätsklinikum Essen, Germany.

Correspondence to Artur-Aron Weber, MD, Institut für Pharmakologie, Universität Duisburg-Essen, Universitätsklinikum Essen, Hufelandstr. 55, D-45122 Essen, Germany. E-mail artur.weber{at}uk-essen.de

Objectives— Apoptotic monocytes release membrane microparticles which may play a major role in thrombogenicity through a P-selectin glycoprotein ligand (PGSL-1)–mediated mechanism. We have studied systematically the regulation of PSGL-1 expression and function in apoptotic monocytic cells.

Methods and Results— PSGL-1 expression (flow cytometry, immunofluorescence microscopy, immunoblot) was virtually abolished in apoptotic monocytes by proteolytic shedding. This was accompanied by a complete loss of PSGL-1–mediated platelet–leukocyte (flow cytometry) and leukocyte–endothelial cell (parallel plate flow chamber) interactions. Systematic screening of protease inhibitors combined with knock-out and siRNA experiments characterized the PSGL-1-cleaving enzyme as an N-ethylmaleimide-inhibitable metalloproteinase of the ADAM family.

Conclusions— Downmodulation of PGSL-1 in apoptotic monocytes may prevent ectopic cell clearance in the peripheral vasculature to reduce local inflammatory and proliferative responses. Depletion of PSGL-1 expression on apoptotic microparticles may also act as a molecular switch to modulate their thrombogenic activity.

We have studied P-selectin glycoprotein ligand (PSGL-1) expression and function in apoptotic monocytic cells. PSGL-1 expression was virtually abolished by proteolytic ectodomain shedding resulting in a complete loss of platelet–leukocyte and leukocyte–endothelial cell interactions. Downmodulation of PGSL-1 may prevent ectopic cell clearance and may act as a molecular switch to reduce thrombogenicity.

Key Words: PSGL-1 • apoptosis • monocytes • platelets • endothelial cells