Brain-to-cervical lymph node signaling after stroke

Elga Esposito, Bum Ju Ahn, Jingfei Shi, Yoshihiko Nakamura, Ji Hyun Park, Emiri T. Mandeville, Zhanyang Yu, Su Jing Chan, Rakhi Desai, Ayumi Hayakawa, Xunming Ji, Eng H. Lo () and Kazuhide Hayakawa ()
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Elga Esposito: Massachusetts General Hospital and Harvard Medical School
Bum Ju Ahn: Massachusetts General Hospital and Harvard Medical School
Jingfei Shi: Massachusetts General Hospital and Harvard Medical School
Yoshihiko Nakamura: Massachusetts General Hospital and Harvard Medical School
Ji Hyun Park: Massachusetts General Hospital and Harvard Medical School
Emiri T. Mandeville: Massachusetts General Hospital and Harvard Medical School
Zhanyang Yu: Massachusetts General Hospital and Harvard Medical School
Su Jing Chan: Massachusetts General Hospital and Harvard Medical School
Rakhi Desai: Massachusetts General Hospital and Harvard Medical School
Ayumi Hayakawa: Massachusetts General Hospital and Harvard Medical School
Xunming Ji: Capital Medical University
Eng H. Lo: Massachusetts General Hospital and Harvard Medical School
Kazuhide Hayakawa: Massachusetts General Hospital and Harvard Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-13324-w

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