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Neutrophil Extracellular Traps may be a Potential Target for Treating Early Brain Injury in Subarachnoid Hemorrhage

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Abstract

Neuroinflammation is closely associated with poor prognosis in patients with subarachnoid hemorrhage (SAH). The purpose of this study was to investigate the role of neutrophil extracellular traps (NETs), which are important regulators of sterile inflammation, in SAH. In this study, markers of NET formation, quantified by the level of citrullinated histone H3 (CitH3), were significantly increased after SAH and correlated with SAH severity. CitH3 peaked at 12 h in peripheral blood and at 24 h in the brain. Administration of the peptidyl arginine deiminase 4 (PAD4) selective antagonist GSK484 substantially attenuated SAH-induced brain edema and neuronal injury. Moreover, the benefit of NET inhibition was also confirmed by DNAse I treatment and neutrophil depletion. Mechanistically, NETs markedly exacerbated microglial inflammation in vitro. NET formation aggravated neuroinflammation by promoting microglial activation and increased the levels of TNF-α, IL-1β, and IL-6, while inhibiting NETs demonstrated anti-inflammatory effects by decreasing the levels of these proinflammatory factors. Moreover, neurogenic pulmonary edema (NPE), a severe nonneurological complication after SAH, is associated with a high level of NET formation. However, GSK484 effectively inhibited the formation of NETs in the lungs of NPE mice, thereby preventing the diffusion of neutrophilic infiltration and attenuating the swelling of the alveolar interstitium. In conclusion, NETs promoted neuroinflammation after SAH, while pharmacological inhibition of PAD4-NETs could reduce the inflammatory damage caused by SAH. These results supported the idea that NETs might be potential therapeutic targets for SAH.

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Data Availability

All raw data used in this manuscript are available on reasonable request.

Abbreviations

SAH:

Subarachnoid hemorrhage

NETs:

Neutrophil extracellular traps

PAD4:

Peptidyl arginine deiminase 4

NPE:

Neurogenic pulmonary edema

CNS:

Central nervous system

ROS:

Reactive oxygen species

CitH3:

Citrullinated histone H3

TBI:

Traumatic brain injury

DNase I:

Deoxyribonuclease-1

PMNs:

Polymorphonuclear leukocytes

MWM:

Morris water maze

ELISA:

Enzyme linked immunosorbent assay

qRT-PCR:

Quantitative real-time polymerase chain reaction

FJC:

Fluoro-jade C

FACS:

Flow cytometric analysis

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Funding

This work was supported by the National Key R&D program of China (2018YFC1312600, 2018YFC1312603), the Key Research and Development Project of Zhejiang Province (no.2018C03011), and the National Natural Science Foundation of China (no.81771246, 81971099, 81870908, 81901234, 81601003, 81801144, 81701152).

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Author notes

  1. Hanhai Zeng, Xiongjie Fu and Jing Cai contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road 88th, Hangzhou, 310000, China

    Hanhai Zeng, Xiongjie Fu, Yucong Peng, Jianfeng Zhuang, Jingyin Chen, Huaijun Chen, Qian Yu, Chaoran Xu, Hang Zhou, Yang Cao, Libin Hu, Jianru Li, Shenglong Cao, Chi Gu, Feng Yan & Gao Chen

  2. Neurosurgerical Intensive Care Unit, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

    Jing Cai

  3. Zhejiang University School of Medicine, Hangzhou, China

    Chenjun Sun & Mengyan Yu

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Contributions

HHZ, XJF, JC, and YCP performed the SAH model and Western blots. CJS, MYY, JFZ, JYC, and HJC prepared the figures. QY, CRX, and YC performed the immunostaining. HZ, LBH, and JRL performed RT-PCR; SLC and CG performed cell culture and data analysis. FY and GC designed experiments. HHZ, JC, CJS, MYY and XJF contributed to the writing and editing of the manuscript. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Feng Yan or Gao Chen.

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All procedures involved animal were conformed to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and were approved by the Institutional Animal Care and Use Committee of Zhejiang University.

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Zeng, H., Fu, X., Cai, J. et al. Neutrophil Extracellular Traps may be a Potential Target for Treating Early Brain Injury in Subarachnoid Hemorrhage. Transl. Stroke Res. 13, 112–131 (2022). https://doi.org/10.1007/s12975-021-00909-1

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