Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Elmar Pieterse, Nils Rother, Marjolein Garsen, Julia M Hofstra, Simon C Satchell, Markus Hoffmann, Markus A Loeven, Hanneke K Knaapen, Olivier W H van der Heijden, Jo H M Berden, Luuk B Hilbrands, Johan van der Vlag

Research output: Contribution to journalArticle (Academic Journal)peer-review

171 Citations (Scopus)


OBJECTIVE: An excessive release and impaired degradation of neutrophil extracellular traps (NETs) leads to the continuous exposure of NETs to the endothelium in a variety of hematologic and autoimmune disorders, including lupus nephritis. This study aims to unravel the mechanisms through which NETs jeopardize vascular integrity.

APPROACH AND RESULTS: Microvascular and macrovascular endothelial cells were exposed to NETs, and subsequent effects on endothelial integrity and function were determined in vitro and in vivo. We found that endothelial cells have a limited capacity to internalize NETs via the receptor for advanced glycation endproducts. An overflow of the phagocytic capacity of endothelial cells for NETs resulted in the persistent extracellular presence of NETs, which rapidly altered endothelial cell-cell contacts and induced vascular leakage and transendothelial albumin passage through elastase-mediated proteolysis of the intercellular junction protein VE-cadherin. Furthermore, NET-associated elastase promoted the nuclear translocation of junctional β-catenin and induced endothelial-to-mesenchymal transition in cultured endothelial cells. In vivo, NETs could be identified in kidney samples of diseased MRL/lpr mice and patients with lupus nephritis, in whom the glomerular presence of NETs correlated with the severity of proteinuria and with glomerular endothelial-to-mesenchymal transition.

CONCLUSIONS: These results indicate that an excess of NETs exceeds the phagocytic capacity of endothelial cells for NETs and promotes vascular leakage and endothelial-to-mesenchymal transition through the degradation of VE-cadherin and the subsequent activation of β-catenin signaling. Our data designate NET-associated elastase as a potential therapeutic target in the prevention of endothelial alterations in diseases characterized by aberrant NET release.

Original languageEnglish
Pages (from-to)1371-1379
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number7
Early online date11 May 2017
Publication statusPublished - 10 Jul 2017

Structured keywords

  • Bristol Heart Institute


  • Adult
  • Animals
  • Antigens, CD
  • Cadherins
  • Capillary Permeability
  • Clathrin
  • Disease Models, Animal
  • Endocytosis
  • Epithelial-Mesenchymal Transition
  • Extracellular Traps
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Kidney Glomerulus
  • Leukocyte Elastase
  • Lupus Nephritis
  • Mice, Inbred CBA
  • Mice, Inbred MRL lpr
  • Neutrophils
  • Phagocytosis
  • Receptor for Advanced Glycation End Products
  • Severity of Illness Index
  • Signal Transduction
  • Time Factors
  • Young Adult
  • beta Catenin
  • Journal Article


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