Drainage of senescent astrocytes from brain via meningeal lymphatic routes
Drainage of senescent astrocytes from brain via meningeal lymphatic routes
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通过脑膜淋巴途径从大脑中排出衰老的星形胶质细胞
DOI：
10.1016/j.bbi.2022.04.005
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发表时间：
2022-04-16
影响因子：
15.1
通讯作者：
Xiao, Ming
中科院分区：
文献类型：
--
作者：
Li, Qian;Chen, Yan;Xiao, Ming
最近关于中枢淋巴系统的研究进展大大增加了我们对大脑如何维持自身废物平衡的理解。在这里，我们发现血管周围空间和脑膜淋巴管形成了一条清除老化大脑中衰老星形胶质细胞的功能途径。结扎颈深淋巴结阻断脑膜淋巴引流，损害脑实质中衰老星形胶质细胞的清除，随后增加老年小鼠的神经炎症。相比之下，通过重组腺相关病毒编码小鼠血管内皮生长因子- c （VEGF-C）增加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。在机制上，VEGF- c在衰老星形细胞中高表达，通过与VEGF受体3相互作用，促进自身沿C-C基序趋化因子配体21 （CCL21）梯度在淋巴管中迁移。此外，池内注射抗CCL21抗体可阻碍衰老星形细胞进入淋巴管，加重老年小鼠的短时记忆缺陷。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中的新视角，从而为治疗干预提供了有价值的靶点。
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.