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

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.