1. Academic Validation
  2. NINJ1-mediated plasma membrane rupture of pyroptotic endothelial cells exacerbates blood-brain barrier destruction caused by neutrophil extracellular traps in traumatic brain injury

NINJ1-mediated plasma membrane rupture of pyroptotic endothelial cells exacerbates blood-brain barrier destruction caused by neutrophil extracellular traps in traumatic brain injury

  • Cell Death Discov. 2025 Feb 20;11(1):69. doi: 10.1038/s41420-025-02350-x.
Xiao-Bo Zheng 1 Xue Wang 2 Sheng-Qing Gao 2 Chao-Chao Gao 3 Tao Li 3 Yan-Ling Han 2 Ran Zhao 2 Yan Sun 3 Shu-Hao Miao 3 Jia-Yin Qiu 2 Wang-Xuan Jin 2 Meng-Liang Zhou 4 5
Affiliations

Affiliations

  • 1 Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China.
  • 2 Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 3 Department of Neurosurgery, Jinling Hospital, Jinling School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
  • 4 Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China. zhoumengliang@nju.edu.cn.
  • 5 Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. zhoumengliang@nju.edu.cn.
Abstract

Brain endothelial cell (bEC) dysfunction is the main factor of blood-brain barrier (BBB) breakdown, which triggers a vicious cycle of aggravating traumatic brain injury (TBI) pathogenesis. Previous studies have revealed that neutrophil extracellular traps (NETs) released by neutrophils can lead to BBB disruption, but there is a lack of research on the underlying mechanisms after TBI. Here, excessive NETs were found in both contused brain tissue and circulation following TBI. We found that NETs could activate the TLR4/NF-κB pathway to induce bEC Pyroptosis, which led to BBB disruption after TBI. During this process, ninjurin-1 (NINJ1) was activated in pyroptotic bECs, and it mediated the release of high mobility group box 1 protein (HMGB1) via plasma membrane rupture (PMR) to promote NET formation. NINJ1-mediated release of HMGB1 aggravated NET accumulation by forming a vicious circle following TBI. Knockdown of NINJ1 rescued NET formation, attenuated BBB leakage, and improved neurological outcomes after TBI. NINJ1 may represent a promising target for alleviating NET-induced BBB destruction and Other related injuries after TBI.

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