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Background <p>Blood-brain barrier (BBB) disruption is a critical pathological event contributing to secondary injury and poor outcomes following traumatic brain injury (TBI). While neutrophil extracellular traps (NETs) are known to exacerbate neuroinflammation, the precise molecular mechanisms by which they compromise cerebral microvascular integrity remain elusive. This study aimed to investigate the role of the NETs-AIM2 inflammasome axis in mediating endothelial damage and to explore the therapeutic potential of targeting this pathway.</p> Methods <p>A controlled cortical impact (CCI) mouse model was utilized to simulate TBI. NET formation was modulated pharmacologically using the peptidylarginine deiminase 4 (PAD4) inhibitor Cl-amidine or genetically via adenoviral overexpression of PAD4. BBB permeability, brain edema, and cerebral blood flow (CBF) were assessed using Evans Blue extravasation, wet-to-dry weight ratio, T2-weighted magnetic resonance imaging, and laser speckle contrast imaging. Neurological function was evaluated via modified Neurological Severity Score (mNSS) and rotarod tests. Molecular mechanisms were dissected using Western blotting, immunofluorescence, and cell-type-specific co-localization analyses.</p> Results <p>TBI induced significant PAD4-dependent NET formation, peaking at day 3 post-injury, which temporally coincided with BBB breakdown and neurological deficits. Cl-amidine treatment effectively preserved tight junction proteins (zonula occludens-1, Occludin) and adherens junction protein (vascular endothelial-cadherin), reduced Evans Blue extravasation, attenuated brain edema and lesion volume, promoted CBF restoration, and improved mNSS scores and rotarod performance. Mechanistically, NETs acted as upstream danger signals that specifically triggered AIM2 inflammasome activation, which was predominantly localized in cerebral microvascular endothelial cells rather than glial cells. This endothelial-specific AIM2 activation subsequently initiated PANoptosis—a multifaceted cell death program characterized by simultaneous pyroptosis, necroptosis, and apoptosis—in the vascular endothelium. Pharmacological inhibition of AIM2 effectively suppressed all three death pathways and preserved BBB integrity. Adenoviral overexpression of PAD4 exacerbated endothelial PANoptosis, whereas AIM2 inhibition reversed these effects, establishing the causal relationship.</p> Conclusions <p>Our findings demonstrate a pathogenic axis wherein TBI-induced NETs drive endothelial PANoptosis via specific activation of the AIM2 inflammasome in cerebral microvascular endothelial cells, leading to BBB failure. Targeting this signaling cascade represents a promising therapeutic strategy to protect the neurovascular unit and improve functional recovery after TBI.</p>

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Neutrophil extracellular traps drive AIM2-mediated endothelial PANoptosis and blood–brain barrier disruption after traumatic brain injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月1日

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  • Haifeng Zhang,
  • Liang Liu,
  • Bingyou Yuan,
  • Hao Chen,
  • Peiyu Li,
  • Yan Chai,
  • Shu Zhang,
  • Xin Chen

摘要

Background

Blood-brain barrier (BBB) disruption is a critical pathological event contributing to secondary injury and poor outcomes following traumatic brain injury (TBI). While neutrophil extracellular traps (NETs) are known to exacerbate neuroinflammation, the precise molecular mechanisms by which they compromise cerebral microvascular integrity remain elusive. This study aimed to investigate the role of the NETs-AIM2 inflammasome axis in mediating endothelial damage and to explore the therapeutic potential of targeting this pathway.

Methods

A controlled cortical impact (CCI) mouse model was utilized to simulate TBI. NET formation was modulated pharmacologically using the peptidylarginine deiminase 4 (PAD4) inhibitor Cl-amidine or genetically via adenoviral overexpression of PAD4. BBB permeability, brain edema, and cerebral blood flow (CBF) were assessed using Evans Blue extravasation, wet-to-dry weight ratio, T2-weighted magnetic resonance imaging, and laser speckle contrast imaging. Neurological function was evaluated via modified Neurological Severity Score (mNSS) and rotarod tests. Molecular mechanisms were dissected using Western blotting, immunofluorescence, and cell-type-specific co-localization analyses.

Results

TBI induced significant PAD4-dependent NET formation, peaking at day 3 post-injury, which temporally coincided with BBB breakdown and neurological deficits. Cl-amidine treatment effectively preserved tight junction proteins (zonula occludens-1, Occludin) and adherens junction protein (vascular endothelial-cadherin), reduced Evans Blue extravasation, attenuated brain edema and lesion volume, promoted CBF restoration, and improved mNSS scores and rotarod performance. Mechanistically, NETs acted as upstream danger signals that specifically triggered AIM2 inflammasome activation, which was predominantly localized in cerebral microvascular endothelial cells rather than glial cells. This endothelial-specific AIM2 activation subsequently initiated PANoptosis—a multifaceted cell death program characterized by simultaneous pyroptosis, necroptosis, and apoptosis—in the vascular endothelium. Pharmacological inhibition of AIM2 effectively suppressed all three death pathways and preserved BBB integrity. Adenoviral overexpression of PAD4 exacerbated endothelial PANoptosis, whereas AIM2 inhibition reversed these effects, establishing the causal relationship.

Conclusions

Our findings demonstrate a pathogenic axis wherein TBI-induced NETs drive endothelial PANoptosis via specific activation of the AIM2 inflammasome in cerebral microvascular endothelial cells, leading to BBB failure. Targeting this signaling cascade represents a promising therapeutic strategy to protect the neurovascular unit and improve functional recovery after TBI.