Brain-to-cervical lymph node signaling after stroke
Esposito, E. Ahn, B.J. Shi, J. Nakamura, Y. Park, J.H. Mandeville, E.T. Yu, Z. Chan, S.J. Desai, R. Hayakawa, A.
Esposito, E.
Ahn, B.J.
Shi, J.
Nakamura, Y.
Park, J.H.
Mandeville, E.T.
Yu, Z.
Desai, R.
Hayakawa, A.
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Alternative Title
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. © 2019, The Author(s).
Keywords
Source Title
Nature Communications
Publisher
Nature Research
Series/Report No.
Collections
Rights
Attribution 4.0 International
Date
2019
DOI
10.1038/s41467-019-13324-w
Type
Article