Brain-to-cervical lymph node signaling after stroke

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 fo...

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Vydáno v:	Nature communications Ročník 10; číslo 1; s. 5306 - 13
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 22.11.2019 Nature Publishing Group Nature Portfolio
Témata:	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 - 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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-019-13324-w