Recent progress on the central lymphatic system has greatly increased our understanding of how the brain maintains its own waste homeostasis. Here, we showed that perivascular spaces and meningeal lymphatic vessels form a functional route for clearance of senescent astrocytes from the aging brain. Blocking meningeal lymphatic drainage by ligation of the deep cervical lymph nodes impaired clearance of senescent astrocytes from brain parenchyma, subsequently increasing neuroinflammation in aged mice. By contrast, enhancing meningeal lymphatic vessel diameter by a recombinant adeno-associated virus encoding mouse vascular endothelial growth factor-C (VEGF-C) improved clearance of senescent astrocytes and mitigated neuroinflammation. Mechanistically, VEGF-C was highly expressed in senescent astrocytes, contributing themselves to migrate across lymphatic vessels along C–C motif chemokine ligand 21 (CCL21) gradient by interacting with VEGF receptor 3. Moreover, intra-cisternal injection of antibody against CCL21 hampered senescent astrocytes into the lymphatic vessels and exacerbated short memory defects of aged mice. Together, these findings reveal a new perspective for the meningeal lymphatics in the removal of senescent astrocytes, thus offering a valuable target for therapeutic intervention.

中央淋巴系统的最新进展极大地增加了我们对大脑如何维持自身废物稳态的理解。在这里，我们发现血管周围空间和脑膜淋巴管形成了清除衰老大脑中衰老星形胶质细胞的功能性途径。通过结扎颈深淋巴结来阻断脑膜淋巴引流会损害脑实质中衰老星形胶质细胞的清除，从而增加老年小鼠的神经炎症。相比之下，通过编码小鼠血管内皮生长因子-C (VEGF-C) 的重组腺相关病毒增强脑膜淋巴管直径可改善衰老星形胶质细胞的清除并减轻神经炎症。机制上，VEGF-C 在衰老的星形胶质细胞中高度表达，通过与 VEGF 受体 3 相互作用，有助于它们沿着 C-C 基序趋化因子配体 21 (CCL21) 梯度迁移穿过淋巴管。此外，脑池内注射抗 CCL21 抗体阻碍了衰老的星形胶质细胞进入淋巴管并加剧了老年人的短记忆缺陷老鼠。总之，这些发现揭示了脑膜淋巴管在去除衰老星形胶质细胞方面的新视角，从而为治疗干预提供了有价值的目标。