Neutrophil elastase-deficient mice form neutrophil extracellular traps in an experimental model of deep vein thrombosis HHS Public Access

  • Martinod K
  • Witsch T
  • Farley K
 et al. 
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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 impact 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 in the inferior vena cava stenosis model of deep vein thrombosis (DVT). Results—NE-deficiency resulted in a small reduction in ionomycin-induced NET formation in vitro without affecting histone citrullination. However, NET production in response to PMA or PAF was normal in neutrophils from two independent NE-deficient mouse lines, or in NE −/− SB1 −/− as compared to SB1 −/− neutrophils. NE-deficiency or inhibition did not prevent NETosis in vivo and DVT outcome. Conclusions—NE 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

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  • Kimberly Martinod

  • Thilo Witsch

  • Kalamo Farley

  • Maureen Gallant

  • Eileen Remold-O 'donnell

  • Denisa D Wagner

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