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Vagus Nerve Stimulation Prevents Endothelial Necroptosis to Alleviate Blood-Spinal Cord Barrier Disruption After Spinal Cord Injury

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Abstract

Vagus nerve stimulation (VNS) is a promising neuromodulation technique, which has been demonstrated to promote functional recovery after spinal cord injury (SCI) in our previous study. But the underlying mechanism remains to be explored. Using a compressed SCI model, our present study first demonstrated that activated microglia produce abundant tumor necrosis factor-α (TNF-α) to induce endothelial necroptosis via receptor-interacting protein kinase 1 (RIP1)/RIP3/mixed lineage kinase domain-like protein (MLKL) pathway, thus destroying the blood-spinal cord barrier (BSCB) after SCI. While both TNF-α specifical antibody (infliximab) and necroptosis inhibitor (necrostatin-1) alleviate BSCB disruption. Then our study found that VNS significantly inhibits microglia-derived TNF-α production and reduces expression of p-RIP3 and p-MLKL in endothelial cells. As expected, further results indicated that VNS mitigates the BSCB disruption, thus reducing inflammatory cells infiltration and neural damage. Finally, both electrophysiological evaluation and locomotor test demonstrated that VNS promotes motor function recovery after SCI. In conclusion, our data demonstrated VNS restricts microglia-derived TNF-α to prevent RIP1/RIP3/MLKL mediated endothelial necroptosis, thus alleviating the decisive pathophysiological BSCB disruption to reduce neuroinflammation and neural damage, which ultimately promotes motor function recovery after SCI. Therefore, these results further elaborate that VNS might be a promising therapeutic strategy for SCI.

Graphical Abstract

Vagus nerve stimulation prevents microglia-derived TNF-α induced endothelial necroptosis to alleviate blood-spinal cord barrier disruption after spinal cord injury.

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Data Availability

All data that support the fndings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by grants 82172542 (H.L.L.) and U19A2082 (J.M.H.) from the National Natural Science Foundation of China, CQYC20210510203 (J.M.H.) from the Chongqing Talents Project, and cst2021jcyj-msxmX0612 (J.M.H.) from the Natural Science Foundation of Chongqing.

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Authors and Affiliations

  1. Department of Rehabilitation, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China

    Hui Chen, Zhou Feng, Lingxia Min, Mingliang Tan, Dongyun Zhang, Qiuwen Gong, Hongliang Liu & Jingming Hou

  2. Department of Rehabilitation, Wusheng Hospital of Traditional Chinese Medicine, Sichuan, China

    Hui Chen

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  1. Hui Chen
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Contributions

Study conception and design: JMH; animal model establishment: LXM, MLT; experiment implementation: HC, ZF, DYZ; manuscript draft: HC, ZF, QWG; critical revision: JMH, HLL. All authors approved the submitted version.

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Correspondence to Jingming Hou.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Third Military Medical University (Army Medical University) for the use of laboratory animals (approval no. AMUWEC20210377).

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Hui Chen and Zhou Feng have contributed equally to this work and share first authorship.

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Chen, H., Feng, Z., Min, L. et al. Vagus Nerve Stimulation Prevents Endothelial Necroptosis to Alleviate Blood-Spinal Cord Barrier Disruption After Spinal Cord Injury. Mol Neurobiol 60, 6466–6475 (2023). https://doi.org/10.1007/s12035-023-03477-7

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