Brain-to-cervical lymph node signaling after stroke

• Published in: Nature communications 2019-11, Vol.10 (1), p.5306-13, Article 5306
• Main Authors: Esposito, Elga, Ahn, Bum Ju, Shi, Jingfei, Nakamura, Yoshihiko, Park, Ji Hyun, Mandeville, Emiri T., Yu, Zhanyang, Chan, Su Jing, Desai, Rakhi, Hayakawa, Ayumi, Ji, Xunming, Lo, Eng H., Hayakawa, Kazuhide
• Format: Article
• Language: English
• Subjects: 38/61; 631/250/1617; 631/250/2503; 631/250/2504/342; 631/250/256/2516; 64/60; 64/86; 82/51; 96/1; 96/21; 96/31; 96/34; 96/63; Animals; Brain; Brain - immunology; Brain - metabolism; Brain damage; Brain Infarction - immunology; Brain Infarction - metabolism; Brain injury; Brain Ischemia - immunology; Brain Ischemia - metabolism; Cell activation; Cell Proliferation; Cerebral infarction; Endothelial Cells; Endothelium; Endothelium, Lymphatic - immunology; Endothelium, Lymphatic - metabolism; Head injuries; Humanities and Social Sciences; Immune system; Infarction; Inflammation; Ischemia; Kinases; Lymph nodes; Lymph Nodes - immunology; Lymph Nodes - metabolism; Lymphangiogenesis; Lymphatic system; Macrophages; Macrophages - immunology; Mice; multidisciplinary; Neck; Protein-tyrosine kinase; Rats; Science; Science (multidisciplinary); Signal transduction; Signaling; Stroke; Stroke - immunology; Stroke - metabolism; Tyrosine; Vascular endothelial growth factor; Vascular Endothelial Growth Factor C - immunology; Vascular Endothelial Growth Factor C - metabolism; Vascular Endothelial Growth Factor Receptor-3 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-3 - immunology; Vascular Endothelial Growth Factor Receptor-3 - metabolism; Vascular endothelial growth factor receptors
• ISSN: 2041-1723; 2041-1723
• 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. Brain damage induces systemic inflammation, but insights and implication of this induction is still unclear. Here the authors show, using rat and mouse focal cerebral ischemia models, that the damaged brain signals via the VEGF-C/VEFGR3 axis to activate inflammatory responses in the draining cervical lymph nodes to induce systemic inflammation.