Inhibition of Transglutaminase 2 Preserves Blood-Brain Barrier Integrity and Improves Neurological Outcomes After Experimental Traumatic Brain Injury in Mice

  • CNS Neurosci Ther. 2026 Apr;32(4):e70887. doi: 10.1002/cns.70887.
Jieru Yang  1  2 ,  Lihan Zhang  1  2 ,  Xiancheng Qiu  1  2 ,  Jiyang Wang  1  2 ,  Ruicheng Yan  1  2 ,  Jiasen Ye  1  2 ,  Jianhua Peng  1  2  3  4 ,  Yong Jiang  1  2  5  6
Affiliations
  • 1. Department of Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou, China.
  • 2. Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou, China.
  • 3. Clinical Trial Research Center, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China.
  • 4. Academician (Expert) Workstation of Sichuan Province, the Affiliated Hospital, Southwest Medical University, Luzhou, China.
  • 5. Institute of Brain Science, Southwest Medical University, Luzhou, China.
  • 6. Sichuan Clinical Research Center for Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou, China.
PMID: 42002982 DOI: 10.1002/cns.70887
Abstract

Background: Traumatic brain injury (TBI) is a leading global cause of disability and mortality, with blood-brain barrier (BBB) disruption exacerbating secondary injury. Transglutaminase 2 (TGM2), a multifunctional enzyme implicated in neuroinflammation and extracellular matrix remodeling, remains underexplored in TBI-related BBB dysfunction. This study elucidates the role of TGM2 in BBB disruption following TBI and explores its therapeutic potential in mitigating BBB damage.

Methods: The controlled cortical impact (CCI) and oxygen-glucose deprivation (OGD) models were used to establish in vivo and in vitro TBI models in mice. The experimental approaches comprised RNA Sequencing, Western blot analysis, RT-qPCR, immunofluorescence staining, and behavioral assessments.

Results: TGM2 expression peaked at 48 h after TBI, predominantly in brain endothelial cells, correlating with BBB disruption (reduced tight junction proteins, increased edema). TGM2 knockdown may attenuate MMP-9 via the IL-17 pathway, restoring BBB integrity. In vivo, TGM2 inhibition reduced Evans blue leakage, upregulated CLAUDIN-5/ZO-1, and improved motor coordination, balance, and spatial memory.

Conclusion: TGM2 is a key molecule affecting the BBB after TBI. Inhibition of TGM2 can alleviate the blood-brain barrier and neurological deficits after TBI, acting through the IL-17-MMP-9 axis.

Keywords
IL‐17; MMP‐9; blood–brain barrier; transglutaminase 2; traumatic brain injury.
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