Blocking cerebral lymphatic system reduces central and peripheral inflammatory response in ischemic stroke

Area of Science:

• Neuroscience
• Immunology
• Vascular Biology

Background:

• Ischemic stroke triggers intracranial inflammation and secondary brain damage.
• Peripheral immune cell activation exacerbates systemic inflammatory responses post-stroke.
• Meningeal lymphatic vessels (LVs) are implicated in central nervous system immune surveillance.

Purpose of the Study:

• To investigate the role of meningeal lymphatics in immune cell infiltration and activation following ischemic stroke.
• To evaluate the therapeutic potential of modulating meningeal lymphatic function in stroke models.

Main Methods:

• Bilateral deep cervical lymph nodes (dCLNs) were removed in Sprague Dawley rats prior to middle cerebral artery occlusion (MCAO).
• Immune cell infiltration in the brain, activation of microglia and astrocytes, and peripheral immune cell populations were assessed.
• Inflammatory cytokine levels in plasma were measured.
• Meningeal lymphatic function was enhanced using adeno-associated virus-vascular endothelial growth factor C (AAV-VEGFC) for reverse validation.

Main Results:

• Blocking meningeal LVs significantly reduced infarct volume and immune cell infiltration in the brain.
• Microglial and pro-inflammatory astrocyte activation was inhibited following dCLN removal.
• Depletion of dCLNs led to decreased CD4+, CD8+ T lymphocytes, B lymphocytes, macrophages, and neutrophils in spleen and blood.
• Levels of inflammatory factors IL-6, IL-10, IL-1β, and TNF-α in plasma were significantly reduced.
• AAV-VEGFC treatment confirmed these findings through reverse validation.

Conclusions:

• Meningeal lymphatics play a critical role in mediating central immune responses and exacerbating brain damage after ischemic stroke.
• Targeting meningeal lymphatic drainage presents a promising therapeutic strategy for mitigating secondary brain injury in stroke.