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

作者：Jieru Yang, Lihan Zhang, Xiancheng Qiu, Jiyang Wang, Ruicheng Yan, Jiasen Ye, Jianhua Peng, Yong Jiang · 发表于：CNS Neuroscience & Therapeutics · 年份：2026 · DOI：10.1002/cns.70887 · 被引用次数：1 · 研究领域：Blood properties and coagulation、Trauma, Hemostasis, Coagulopathy, Resuscitation、Hemoglobin structure and function

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.