Meningeal Lymphatics Drives Macrophage Clearance via CCL2-CCR2 Axis After Cerebral Ischemia

Area of Science:

• Neuroimmunology
• Vascular Biology
• Stroke Pathophysiology

Background:

• The role of meningeal lymphatic vessels (mLVs) in post-stroke immune cell clearance is not fully understood.
• Understanding immune cell trafficking in the meninges after ischemic stroke is crucial for developing effective therapies.

Purpose of the Study:

• To elucidate the mechanisms of immune cell clearance mediated by mLVs after stroke.
• To investigate the role of the CCL2-CCR2 axis in macrophage recruitment to mLVs.
• To evaluate the therapeutic potential of enhancing mLV function and modulating the CCL2-CCR2 axis.

Main Methods:

• Single-cell RNA sequencing of post-ischemic meningeal macrophages in a mouse stroke model.
• In vitro co-culture experiments and pharmacological inhibition of CCR2 (RS504393).
• Assessment of macrophage trafficking using Evans Blue tracing and immunofluorescence; evaluation of neurological deficits, brain edema, and neuroinflammation.

Main Results:

• Ischemia leads to an expansion of meningeal macrophages, with their interaction with lymphatic endothelial cells dependent on the CCL2-CCR2 axis.
• CCR2 inhibition disrupted macrophage trafficking to mLVs and lymph nodes, exacerbating stroke outcomes.
• VEGF-C treatment improved mLV drainage and ameliorated neurological deficits, brain edema, and neuroinflammation.

Conclusions:

• Meningeal lymphatic vessels recruit macrophages via CCL2 for perivascular clearance post-ischemia.
• Targeting the CCL2-CCR2 axis and enhancing mLV function represent a promising synergistic therapeutic approach for stroke.