The Gas6-Axl Interaction Mediates Endothelial Uptake of Platelet Microparticles.

Happonen, Kaisa E; Tran, Sinh; Morgelin, Matthias; Prince, Raja; Calzavarini, Sara; Angelillo, Anne; Dahlback, Bjorn (2016). The Gas6-Axl Interaction Mediates Endothelial Uptake of Platelet Microparticles. Journal of biological chemistry, 291(20), pp. 10586-10601. American Society for Biochemistry and Molecular Biology 10.1074/jbc.M115.699058

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Upon activation, platelets release plasma-membrane derived microparticles (PMPs) exposing phosphatidylserine (PS) on their surface. The function and clearance mechanism of these MPs are incompletely understood. As they are pro-coagulant and potentially pro-inflammatory, rapid clearance from the circulation is essential for prevention of thrombotic diseases. The tyrosine kinase receptors Tyro3, Axl and Mer (TAMs) and their ligands protein S and Gas6 are involved in the uptake of PS-exposing apoptotic cells in macrophages and dendritic cells. Both TAMs and their ligands are expressed in the vasculature, the functional significance of which is poorly understood. In this study we investigated how vascular TAMs and their ligands may mediate endothelial uptake of PMPs. PMPs, generated from purified human platelets, were isolated by ultracentrifugation and labeled with biotin or PKH67. The uptake of labeled MPs in the presence of protein S and Gas6 in human aortic endothelial cells (HAEC) and human umbilical vein endothelial cells (HUVEC) was monitored by flow cytometry, western blotting and confocal/electron microscopy. We found that both endothelial cell types can phagocytose PMPs, and using TAM-blocking antibodies or siRNA knock-down of individual TAMs we show that the uptake is mediated by endothelial Axl and Gas6. As circulating PMPs-levels were not altered in Gas6-/- mice compared to Gas6+/+ mice, we hypothesize that the Gas6-mediated uptake is not a means to clear the bulk of circulating PMPs but may serve to phagocytose PMPs locally generated at sites of platelet activation and as a way to affect endothelial responses.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Hämatologie (Erwachsene)

UniBE Contributor:

Prince, Raja; Calzavarini, Sara and Angelillo, Anne

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0021-9258

Publisher:

American Society for Biochemistry and Molecular Biology

Language:

English

Submitter:

Verena Zwahlen

Date Deposited:

31 Mar 2016 16:40

Last Modified:

23 Mar 2017 02:30

Publisher DOI:

10.1074/jbc.M115.699058

PubMed ID:

27006397

Uncontrolled Keywords:

Axl; Gas6; endothelium; extracellular vesicles; microparticles; phagocytosis; platelet

BORIS DOI:

10.7892/boris.80418

URI:

https://boris.unibe.ch/id/eprint/80418

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