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Brain-to-cervical lymph node signaling after stroke

Author

Listed:
  • 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
    Capital Medical University)

  • Yoshihiko Nakamura

    (Massachusetts General Hospital and Harvard Medical School
    Fukuoka University Hospital)

  • 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
    National University Health System, National University of Singapore)

  • 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)

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.

Suggested Citation

  • 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 & Kazuhide Hayak, 2019. "Brain-to-cervical lymph node signaling after stroke," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13324-w
    DOI: 10.1038/s41467-019-13324-w
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