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Interaction of factor VII activating protease (FSAP) with neutrophil extracellular traps (NETs)

Grasso, Simona; Neumann, Ariane LU ; Lang, Irene M.; Etscheid, Michael; von Köckritz-Blickwede, Maren and Kanse, Sandip M. (2018) In Thrombosis Research 161. p.36-42
Abstract

The circulating zymogen form of Factor VII activating protease (FSAP) can be activated by histones and nucleosomes in vivo. These cell-death-associated nuclear factors are also actively extruded into the extracellular space by neutrophils through a process called neutrophil extracellular trap (NET) formation (NETosis). NETs are thought to be involved in host defense, inflammation as well as thrombosis. We have investigated the bidirectional interactions of FSAP and NETs. Phorbol ester-mediated NET formation was marginally stimulated by FSAP. Plasma-derived FSAP as well as exogenous FSAP bound to NETs. There was co-localization of FSAP and NETs in coronary thrombi from patients with acute myocardial infarction. Contrary to our... (More)

The circulating zymogen form of Factor VII activating protease (FSAP) can be activated by histones and nucleosomes in vivo. These cell-death-associated nuclear factors are also actively extruded into the extracellular space by neutrophils through a process called neutrophil extracellular trap (NET) formation (NETosis). NETs are thought to be involved in host defense, inflammation as well as thrombosis. We have investigated the bidirectional interactions of FSAP and NETs. Phorbol ester-mediated NET formation was marginally stimulated by FSAP. Plasma-derived FSAP as well as exogenous FSAP bound to NETs. There was co-localization of FSAP and NETs in coronary thrombi from patients with acute myocardial infarction. Contrary to our expectations no activation of pro-FSAP by NETs was evident. However, after disintegration of NETs with DNase, a robust activation of pro-FSAP, due to release of histones from nucleosomes, was detected. The released histones were in turn degraded by FSAP. Histone cytotoxicity towards endothelial cells was neutralized by FSAP more potently than by activated protein C (APC). One more consequence of histone degradation was a decrease in nucleosome release from apoptotic neutrophils. Taken together, NETs bind to FSAP, but do not activate pro-FSAP unless histones are released from NETs by DNAse. This activation of FSAP is likely to be important in diminishing the cytotoxic effect of histones, thus limiting the damaging effect of NETosis.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
FSAP, Inflammation, NETs, Thrombosis
in
Thrombosis Research
volume
161
pages
7 pages
publisher
Elsevier Ltd
external identifiers
  • scopus:85034817331
ISSN
0049-3848
DOI
10.1016/j.thromres.2017.11.012
language
English
LU publication?
yes
id
bf7ecf67-87be-4c2e-90eb-2f9eb1e7d4fb
date added to LUP
2017-12-21 09:42:24
date last changed
2018-01-07 12:29:37
@article{bf7ecf67-87be-4c2e-90eb-2f9eb1e7d4fb,
  abstract     = {<p>The circulating zymogen form of Factor VII activating protease (FSAP) can be activated by histones and nucleosomes in vivo. These cell-death-associated nuclear factors are also actively extruded into the extracellular space by neutrophils through a process called neutrophil extracellular trap (NET) formation (NETosis). NETs are thought to be involved in host defense, inflammation as well as thrombosis. We have investigated the bidirectional interactions of FSAP and NETs. Phorbol ester-mediated NET formation was marginally stimulated by FSAP. Plasma-derived FSAP as well as exogenous FSAP bound to NETs. There was co-localization of FSAP and NETs in coronary thrombi from patients with acute myocardial infarction. Contrary to our expectations no activation of pro-FSAP by NETs was evident. However, after disintegration of NETs with DNase, a robust activation of pro-FSAP, due to release of histones from nucleosomes, was detected. The released histones were in turn degraded by FSAP. Histone cytotoxicity towards endothelial cells was neutralized by FSAP more potently than by activated protein C (APC). One more consequence of histone degradation was a decrease in nucleosome release from apoptotic neutrophils. Taken together, NETs bind to FSAP, but do not activate pro-FSAP unless histones are released from NETs by DNAse. This activation of FSAP is likely to be important in diminishing the cytotoxic effect of histones, thus limiting the damaging effect of NETosis.</p>},
  author       = {Grasso, Simona and Neumann, Ariane and Lang, Irene M. and Etscheid, Michael and von Köckritz-Blickwede, Maren and Kanse, Sandip M.},
  issn         = {0049-3848},
  keyword      = {FSAP,Inflammation,NETs,Thrombosis},
  language     = {eng},
  pages        = {36--42},
  publisher    = {Elsevier Ltd},
  series       = {Thrombosis Research},
  title        = {Interaction of factor VII activating protease (FSAP) with neutrophil extracellular traps (NETs)},
  url          = {http://dx.doi.org/10.1016/j.thromres.2017.11.012},
  volume       = {161},
  year         = {2018},
}