Neutrophil extracellular traps released by neutrophils impair revascularization and vascular remodeling after stroke

Nat Commun. 2020 May 19;11(1):2488. doi: 10.1038/s41467-020-16191-y.

Abstract

Neovascularization and vascular remodeling are functionally important for brain repair after stroke. We show that neutrophils accumulate in the peri-infarct cortex during all stages of ischemic stroke. Neutrophils producing intravascular and intraparenchymal neutrophil extracellular traps (NETs) peak at 3-5 days. Neutrophil depletion reduces blood-brain barrier (BBB) breakdown and enhances neovascularization at 14 days. Peptidylarginine deiminase 4 (PAD4), an enzyme essential for NET formation, is upregulated in peri-ischemic brains. Overexpression of PAD4 induces an increase in NET formation that is accompanied by reduced neovascularization and increased BBB damage. Disruption of NETs by DNase 1 and inhibition of NET formation by genetic ablation or pharmacologic inhibition of PAD increases neovascularization and vascular repair and improves functional recovery. Furthermore, PAD inhibition reduces stroke-induced STING-mediated production of IFN-β, and STING knockdown and IFN receptor-neutralizing antibody treatment reduces BBB breakdown and increases vascular plasticity. Collectively, our results indicate that NET release impairs vascular remodeling during stroke recovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / blood supply
  • Brain / metabolism*
  • Disease Models, Animal
  • Extracellular Traps / genetics
  • Extracellular Traps / metabolism*
  • Humans
  • Interferon-beta / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / metabolism*
  • Protein-Arginine Deiminase Type 4 / genetics
  • Protein-Arginine Deiminase Type 4 / metabolism
  • Stroke / genetics
  • Stroke / metabolism*
  • Vascular Remodeling*

Substances

  • Membrane Proteins
  • Sting1 protein, mouse
  • Interferon-beta
  • Protein-Arginine Deiminase Type 4
  • peptidylarginine deiminase 4, mouse