Brain-to-cervical lymph node signaling after stroke.
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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.
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Blockage of VEGFR3 in mice following focal cerebral ischemia resulted in reduced inflammatory response and infarct, while VEGFR3 mutant mice subjected to MCAO develop larger stroke volumes and worsened edema.
“Blockage of VEGFR3 (expressed by lymphatic endothelial cells) in mice following focal cerebral ischemia resulted in reduced inflammatory response and infarct”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Esposito et al., 2019
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Self-citationSystemic Inflammation after Aneurysmal Subarachnoid Hemorrhage
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Neuroinflammation-Driven Lymphangiogenesis in CNS Diseases
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VEGF-C promotes brain-derived fluid drainage, confers neuroprotection, and improves stroke outcomesPreprint
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CCN1 Is a Therapeutic Target for Reperfused Ischemic Brain Injury
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Meningeal lymphatics can influence stroke outcome
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The glymphatic system in Huntington's disease
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Immune System of the Ischemic Brain: Old Paradigms Revisited
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Self-citationBufotalin ameliorates ovalbumin-induced allergic rhinitis by restoring the Tregs
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Incidence de la circulation lymphatique méningée sur la réponse à un accident vasculaire cérébral
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Social stress induces autoimmune responses against the brain to promote stress susceptibilityPreprint
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Thoracic lymph collection impacts the level of endogenous macromolecules in rat biological fluids
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- Authors
- Esposito, E., Ahn, B. J., Shi, J., Nakamura, Y., Park, J. H., Mandeville, E. T., Yu, Z., Chan, S. J., Desai, R., Hayakawa, A., Ji, X., Lo, E. H., & Hayakawa, K.
- Affiliations
- Harvard University (US)
- Capital Medical University (CN)
- Corresponding author
- Lo, Eng H.
- Hayakawa, Kazuhide
- ORCID
- Venue
- Nature Communications
- Published
- 2019-11-22
- Volume
- 10
- Issue
- 1
- Pages
- 5306-5306
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6876639
- OpenAlex
- W2990744279
- Cited by
- 123
- References
- 70
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 18 · 2023: 16 · 2022: 27 · 2021: 24 · 2020: 5
- FWCI
- 5.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke
- Topics
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Keywords
- stroke, cervical lymph nodes, focal cerebral ischemia, systemic inflammation, lymphatic endothelial cells, macrophage activation, infarct size, lymphatic drainage
- MeSH terms
- Animals, Brain, Brain Ischemia, Endothelium, Lymphatic, Inflammation, Lymph Nodes, Macrophages, Neck, Brain Infarction, Stroke, Vascular Endothelial Growth Factor Receptor-3, Vascular Endothelial Growth Factor C, Lymphangiogenesis, Endothelial Cells, Cell Proliferation, Mice, Rats
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