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Neutrophil Extracellular Traps Exacerbate Ischemic Brain Damage

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Abstract

Most acute strokes are ischemic, and subsequent neuroinflammation promotes further damage leading to cell death but also plays a beneficial role by promoting cellular repair. Neutrophils are forerunners to brain lesions after ischemic stroke and exert elaborate functions. While neutrophil extracellular traps (NETs) possess a fundamental antimicrobial function within the innate immune system under physiological circumstances, increasing evidence indicates that NETosis, the release process of NETs, occurs in the pathogenic process of stroke. In this review, we focus on the processes of NET formation and clearance, the temporal and spatial alterations of neutrophils and NETs after ischemic damage, and how NETs are involved in several stroke-related phenomena. Generally, NET formation and release processes depend on the generation of reactive oxygen species (ROS) and the activation of nuclear peptidylarginine deiminase-4 (PAD4). The acid–base environment, oxygen concentration, and iron ions around the infarct may also impact NET formation. DNase 1 has been identified as the primary degrader of NETs in serum, while reactive microglia are expected to inhibit the formation of NETs around ischemic lesions by phagocytosis of neutrophils. The neutrophils and NETs are present in the perivascular space ipsilateral to the infarct arising after ischemic damage, peaking between 1 and 3 days postischemia, but their location in the brain parenchyma remains controversial. After the ischemic injury, NETs are involved in the destruction of neurological function primarily by disrupting the blood–brain barrier and promoting thrombosis. The potential effects of NETs on various ischemic nerve cells need to be further investigated, especially in the chronic ischemic phase.

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Acknowledgements

We thank Dr Zhanzhuang Tian and Dr Jun Wang from Shanghai Medical College, Fudan University for their valuable comments and suggestions.

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This work was supported by the National Natural Science Foundation of China [grant number 82072540].

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  1. Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Jing’an District, Shanghai, 200040, China

    Congqin Li, Ying Xing, Yuqian Zhang, Yan Hua, Jian Hu & Yulong Bai

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Congqin Li and Yulong Bai had the initial idea for this article; Congqin Li prepared figures and drafted the manuscript; Ying Xing and Yuqian Zhang performed the literature search. All of the authors critically revised the manuscript. Yulong Bai approved the final version of the manuscript and provided the funds.

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Li, C., Xing, Y., Zhang, Y. et al. Neutrophil Extracellular Traps Exacerbate Ischemic Brain Damage. Mol Neurobiol 59, 643–656 (2022). https://doi.org/10.1007/s12035-021-02635-z

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