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The Gas6-Axl Interaction Mediates Endothelial Uptake of Platelet Microparticles

Happonen, Kaisa E LU ; Tran, Sinh LU ; Mörgelin, Matthias LU ; Prince, Raja; Calzavarini, Sara; Angelillo-Scherrer, Anne and Dahlbäck, Björn LU (2016) In Journal of Biological Chemistry 291(20). p.10586-10601
Abstract

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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
291
issue
20
pages
10586 - 10601
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • Scopus:84969245853
ISSN
1083-351X
DOI
10.1074/jbc.M115.699058
language
English
LU publication?
yes
id
a33899c9-763a-41d5-b3b7-32b4b488e53b
date added to LUP
2016-04-11 15:43:00
date last changed
2016-11-20 04:32:27
@misc{a33899c9-763a-41d5-b3b7-32b4b488e53b,
  abstract     = {<p>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.</p>},
  author       = {Happonen, Kaisa E and Tran, Sinh and Mörgelin, Matthias and Prince, Raja and Calzavarini, Sara and Angelillo-Scherrer, Anne and Dahlbäck, Björn},
  issn         = {1083-351X},
  language     = {eng},
  month        = {03},
  number       = {20},
  pages        = {10586--10601},
  publisher    = {ARRAY(0x8756ad0)},
  series       = {Journal of Biological Chemistry},
  title        = {The Gas6-Axl Interaction Mediates Endothelial Uptake of Platelet Microparticles},
  url          = {http://dx.doi.org/10.1074/jbc.M115.699058},
  volume       = {291},
  year         = {2016},
}