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Peer-reviewedCC BY-NC-NDCell communication and signaling : CCS

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

  • Haifeng Zhang1,2
  • Liang Liu1,2
  • Bingyou Yuan1,2
  • Hao Chen1,2
  • Peiyu Li1,2
  • Yan Chai3
  • Shu Zhang4,5
  • Xin Chen6,7
7 affiliations
  1. 1Department of Neurosurgery, Tianjin Medical University General Hospital, No.154, Anshan Road, Tianjin, 300052, P.R. China.
  2. 2Tianjin Neurological Institute, Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, P.R. China.
  3. 3Tianjin Neurological Institute, Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, P.R. China. [email protected].
  4. 4Department of Neurosurgery, Tianjin Medical University General Hospital, No.154, Anshan Road, Tianjin, 300052, P.R. China. [email protected].
  5. 5Tianjin Neurological Institute, Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, P.R. China. [email protected].
  6. 6Department of Neurosurgery, Tianjin Medical University General Hospital, No.154, Anshan Road, Tianjin, 300052, P.R. China. [email protected].
  7. 7Tianjin Neurological Institute, Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, P.R. China. [email protected].
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026neutrophil,
  title = {{Neutrophil extracellular traps drive AIM2-mediated endothelial PANoptosis and blood-brain barrier disruption after traumatic brain injury.}},
  author = {Haifeng Zhang and Liang Liu and Bingyou Yuan and Hao Chen and Peiyu Li and Yan Chai and Shu Zhang and Xin Chen},
  journal = {Cell communication and signaling : CCS},
  year = {2026},
  month = aug,
  doi = {10.1186/s12964-026-03123-4},
  url = {https://europepmc.org/article/MED/42963801},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Neutrophil extracellular traps drive AIM2-mediated endothelial PANoptosis and blood-brain barrier disruption after traumatic brain injury.
AU  - Haifeng Zhang
AU  - Liang Liu
AU  - Bingyou Yuan
AU  - Hao Chen
AU  - Peiyu Li
AU  - Yan Chai
AU  - Shu Zhang
AU  - Xin Chen
PY  - 2026
DA  - 2026/08/01
JO  - Cell communication and signaling : CCS
DO  - 10.1186/s12964-026-03123-4
UR  - https://europepmc.org/article/MED/42963801
AB  - 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.
SN  - 1478-811X
ER  -