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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
1   CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, USA
2   Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA
,
Wolfgang Bergmeier
1   CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, USA
2   Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA
,
Ian S. Patten
1   CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, USA
,
Junichi Hirahashi
3   Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
,
Tanya N. Mayadas
3   Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
,
Denisa D. Wagner
1   CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, USA
2   Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA
› Author AffiliationsFinancial support: This work was supported by National Institutes of Health, National Heart, Lung, and Blood Institute grants R37 HL41002 and P01 HL066105 (D.D.W.) and P01 HL 036028 (T.N.M.); National Institute of Arthritis and Musculoskeletal and Skin Diseases grant AR050800–03 (T.N.M.); and American Heart Association Scientist Development Grant 0630044N (W.B.).
Further Information

Publication History

Received 19 March 2007

Accepted after resubmission 12 July 2007

Publication Date:
01 December 2017 (online)

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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
 

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