Neutrophil elastase-deficient mice form neutrophil extracellular traps in an
experimental model of deep vein thrombosis
#MMPMID26712312
Martinod K
; Witsch T
; Farley K
; Gallant M
; Remold-O'Donnell E
; Wagner DD
J Thromb Haemost
2016[Mar]; 14
(3
): 551-8
PMID26712312
show ga
ESSENTIALS: Neutrophil elastase (NE) plays a role in extracellular trap formation
(NETosis) triggered by microbes. The contribution of NE was evaluated in mouse
NETosis models of sterile inflammation and thrombosis. NE is not required for
mouse neutrophil NET production in vitro with non-infectious stimuli. NE
deficiency had no significant effect on thrombosis in the inferior vena cava
stenosis model. BACKGROUND: Neutrophil serine proteases have been implicated in
coagulation and neutrophil extracellular trap (NET) formation. In human
neutrophils, neutrophil elastase (NE) translocates to the nucleus during NETosis
and cleaves histones, thus aiding in chromatin decondensation. NE(-/-) mice were
shown not to release NETs in response to microbes. However, mouse studies
evaluating the role of NE in NET formation in sterile inflammation and thrombosis
are lacking. OBJECTIVE: We wished to establish if neutrophils from NE(-/-) mice
have a defect in NETosis, similar to peptidylarginine deiminase 4 (PAD4(-/-))
mice, and how this might have an impact on venous thrombosis, a model where NETs
are produced and are crucial to thrombus development. METHODS: We performed in
vitro NET assays using neutrophils from wild-type (WT), NE(-/-), SerpinB1
(SB1)(-/-) and NE(-/-) SB1(-/-) mice. We compared WT and NE(-/-) animals using
the inferior vena cava stenosis model of deep vein thrombosis (DVT). RESULTS:
Neutrophil elastase deficiency resulted in a small reduction in ionomycin-induced
NET formation in vitro without affecting histone citrullination. However, NET
production in response to phorbol 12-myristate 13-acetate or platelet activating
factor was normal in neutrophils from two independent NE-deficient mouse lines,
and in NE(-/-) SB1(-/-) as compared with SB1(-/-) neutrophils. NE deficiency or
inhibition did not prevent NETosis in vivo or DVT outcome. CONCLUSIONS:
Neutrophil elastase is not required for NET formation in mice. NE(-/-) mice,
which form pathological venous thrombi containing NETs, do not phenocopy
PAD4(-/-) mice in in vitro NETosis assays or experimental venous thrombosis. Our
study suggests that NET-targeted therapies need to be highly effective to have an
impact on DVT.
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