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

Lijing Kang, Huilin Yu, Xing Yang, Yuanbo Zhu, Xiaofei Bai, Ranran Wang, Yongliang Cao, Haochen Xu, Haiyu Luo, Lu Lu, Mei-Juan Shi, Yujing Tian, Wenying Fan () and Bing-Qiao Zhao ()
Additional contact information
Lijing Kang: Fudan University
Huilin Yu: Fudan University
Xing Yang: Fudan University
Yuanbo Zhu: Fudan University
Xiaofei Bai: Fudan University
Ranran Wang: Fudan University
Yongliang Cao: Fudan University
Haochen Xu: Fudan University
Haiyu Luo: Fudan University
Lu Lu: Fudan University
Mei-Juan Shi: Fudan University
Yujing Tian: Fudan University
Wenying Fan: Fudan University
Bing-Qiao Zhao: Fudan University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16191-y

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