Meningeal Lymphatic LTBR Deficiency Links Spinal Cord Injury to Secondary Brain Pathology

Spinal cord injury (SCI) induces secondary brain pathology, but the mechanisms linking spinal and brain injury remain unclear. Here, we identify meningeal lymphatic dysfunction as a contributor to secondary brain pathology after SCI. In mice, meningeal lymphatic vessels (mLVs) progressively deteriorated from 14 to 56 days post-injury, accompanied by glymphatic dysfunction. In patients with SCI, diffusion tensor imaging along the perivascular space (DTI-ALPS) revealed impaired glymphatic function, which correlated with motor cortical and hippocampal atrophy. mLVs ablation exacerbated neuroinflammation, neuronal loss, impaired hippocampal neurogenesis, and motor and cognitive deficits, whereas VEGF-C-mediated lymphatic restoration ameliorated these abnormalities. Integrated single-cell and bulk transcriptomics identified reduced LTBR expression in meningeal lymphatic endothelial cells (LECs) after SCI. Ltbr knockdown in LECs further exacerbated SCI-induced lymphatic dysfunction and secondary brain pathology, whereas LEC-specific Ltbr overexpression promoted lymphatic repair and improved neurological outcomes. In human LECs, LTBR enhanced proliferation, migration, and tube formation, with PI3K-AKT signaling potentially contributing to these effects. These findings establish meningeal lymphatic dysfunction as an important component of secondary brain pathology after SCI and identify LTBR as a potential regulator of lymphatic repair.