Meningeal lymphatic ablation reduces ischemic stroke-induced inflammation via reprograming transcriptome profiling in cervical lymph nodes [RNA-seq]

Meningeal lymphatic system governs immune cell trafficking in the brain via brain-to-cervical lymph node (CLN) pathway. However, the role of meningeal lymphatics in brain–CLN axis after stroke remains unclear. Here, we showed that meningeal lymphatic ablation (MLA) reduced brain infarct and neuronal loss levels and inhibited inflammatory pathways in the hippocampus after MCAO–reperfusion. Single-cell transcriptome analysis demonstrated that MLA reduced monocyte/macrophage and polymorphonuclear cell counts and T and natural killer cell effector function. MLA reprogrammed the transcriptome profile related to chemotaxis and leukocyte migration in CLN LECs and downregulated expression of the CCN1 in floor LECs. Mechanistically, MLA inhibited inflammatory macrophage infiltration by repressing CCN1 and CD147 (thromboinflammatory marker) expression in blood vessels, thus inhibiting detrimental inflammatory responses. Blockade of VEGF-C-mediated signaling in meningeal lymphatic system improved memory function after ischemic stroke. Collectively, MLA reprograms the LEC transcriptome and inhibits CCN1-mediated proinflammatory responses during poststroke brain–CLN signaling.