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.
|Number of pages||12|
|Journal||Brain, Behavior, and Immunity|
|State||Published - Jul 2022|
Bibliographical noteFunding Information:
This work was supported by grants from the National Natural Science Foundation of China (no. 81871117 and 31900726) and Natural Science Foundation of Jiangsu Province (no. BK20190655).
© 2022 Elsevier Inc.
- Meningeal lymphatic vessels
- Senescent astrocytes
- VEGF-C/CCL21 pathway
ASJC Scopus subject areas
- Endocrine and Autonomic Systems
- Behavioral Neuroscience