Brain-to-cervical lymph node signaling after stroke

Author:

Esposito Elga,Ahn Bum Ju,Shi Jingfei,Nakamura YoshihikoORCID,Park Ji Hyun,Mandeville Emiri T.ORCID,Yu Zhanyang,Chan Su JingORCID,Desai Rakhi,Hayakawa Ayumi,Ji Xunming,Lo Eng H.,Hayakawa Kazuhide

Abstract

AbstractAfter 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.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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