PSGL-1 regulates platelet P-selectin-mediated endothelial activation and shedding of P-selectin from activated platelets

Vandana S. Dole; Wolfgang Bergmeier; Ian S. Patten; Junichi Hirahashi; Tanya N. Mayadas; Denisa D. Wagner

doi:10.1160/TH07-03-0207

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 98(04): 806-812
DOI: 10.1160/TH07-03-0207

Platelets and Blood Cells

Schattauer GmbH

PSGL-1 regulates platelet P-selectin-mediated endothelial activation and shedding of P-selectin from activated platelets

Vandana S. Dole

¹CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, USA

²Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

,

Wolfgang Bergmeier

¹CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, USA

²Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

,

Ian S. Patten

¹CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, USA

,

Junichi Hirahashi

³Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

,

Tanya N. Mayadas

³Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

,

Denisa D. Wagner

¹CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, USA

²Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

› Author Affiliations

Abstract

Summary

We have previously shown that activated platelets in circulation stimulate release of endothelial Weibel-Palade bodies thus increasing leukocyte rolling in venules. P-selectin on the activated platelets mediates adhesion to leukocytes via PSGL-1 and is rapidly shed into plasma. We were interested in studying the role of PSGL-1 in regulating expression and function of platelet P-selectin. We show here that PSGL-1 is critical for the activation of endothelial cells in venules of mice infused with activated platelets. The interaction of platelet P-selectin with PSGL-1 is also required for P-selectin shedding, as P-selectin was retained significantly longer on the surface of activated platelets infused into PSGL-1^-/- compared to wild-type mice. The leukocyte integrin αMβ2 (Mac-1) was not required for P-selectin shedding. In addition to shedding, P-selectin can be downregulated from the platelet surface through internalization and this is the predominant mechanism in the absence of PSGL-1. We demonstrate that leukocyte- neutrophil elastase,known to cleave P-selectin in vitro, is not the major sheddase for P-selectin in vivo. In conclusion, interaction of platelet P-selectin with PSGL-1 is crucial for activation of the endothelium andWeibel-Palade body secretion. The interaction with PSGL-1 also results in rapid shedding of P-selectin thus downregulating the inflammatory potential of the platelet.

Keywords

PSGL-1 - P-selectin - shedding - platelets - endothelial-activation

Full Text

References

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