Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China.
Nat Commun. 2019 Nov 22;10(1):5306. doi: 10.1038/s41467-019-13324-w.
After stroke, peripheral immune cells are activated and these systemic responses may amplify brain damage, but how the injured brain sends out signals to trigger systemic inflammation remains unclear. Here we show that a brain-to-cervical lymph node (CLN) pathway is involved. In rats subjected to focal cerebral ischemia, lymphatic endothelial cells proliferate and macrophages are rapidly activated in CLNs within 24 h, in part via VEGF-C/VEGFR3 signalling. Microarray analyses of isolated lymphatic endothelium from CLNs of ischemic mice confirm the activation of transmembrane tyrosine kinase pathways. Blockade of VEGFR3 reduces lymphatic endothelial activation, decreases pro-inflammatory macrophages, and reduces brain infarction. In vitro, VEGF-C/VEGFR3 signalling in lymphatic endothelial cells enhances inflammatory responses in co-cultured macrophages. Lastly, surgical removal of CLNs in mice significantly reduces infarction after focal cerebral ischemia. These findings suggest that modulating the brain-to-CLN pathway may offer therapeutic opportunities to ameliorate systemic inflammation and brain injury after stroke.
中风后，外周免疫细胞被激活，这些全身反应可能会加重脑损伤，但受损的大脑如何发出信号引发全身炎症仍不清楚。在这里，我们展示了一个涉及脑到颈部淋巴结（CLN）途径的机制。在接受局灶性脑缺血的大鼠中，在 24 小时内，CLN 中的淋巴内皮细胞增殖，巨噬细胞迅速被激活，部分通过 VEGF-C/VEGFR3 信号通路。从缺血性小鼠的 CLN 中分离的淋巴管内皮的微阵列分析证实了跨膜酪氨酸激酶通路的激活。阻断 VEGFR3 可减少淋巴管内皮细胞的激活，减少促炎巨噬细胞，并减少脑梗死。在体外，淋巴管内皮细胞中的 VEGF-C/VEGFR3 信号可增强共培养的巨噬细胞中的炎症反应。最后，在小鼠中进行 CLN 的手术切除可显著减少局灶性脑缺血后的梗死。这些发现表明，调节脑到 CLN 途径可能为改善中风后全身炎症和脑损伤提供治疗机会。
