CCL2 upregulation triggers hypoxic preconditioning-induced protection from stroke

Area of Science:

• Neuroscience
• Immunology
• Vascular Biology

Background:

• Systemic hypoxia preconditioning (HPC) reduces stroke damage.
• CCL2 (MCP-1) is a chemokine upregulated by hypoxia.
• HPC-induced ischemic tolerance may depend on CCL2.

Purpose of the Study:

• To investigate the role of CCL2 in HPC-induced ischemic tolerance.
• To determine the cellular sources and temporal expression of CCL2 following HPC.
• To assess the impact of CCL2 deficiency on HPC-mediated neuroprotection.

Main Methods:

• Used wild-type and CCL2-null mice.
• Administered HPC (hypoxic preconditioning) prior to middle cerebral artery occlusion (tMCAo).
• Measured CCL2/CCR2 expression, circulating leukocytes, and infarct volume.
• Used CCL2 immunoneutralization to block chemokine activity.

Main Results:

• Cortical CCL2 expression peaked early in neurons, with delayed expression in endothelial cells.
• HPC reduced circulating CCR2+ monocytes in a CCL2-dependent manner.
• CCL2-null mice lacked HPC-induced protection against stroke; blocking CCL2 abolished tolerance.

Conclusions:

• CCL2 upregulation in neurons and endothelial cells is crucial for HPC-induced ischemic tolerance.
• CCL2-mediated effects on circulating monocytes are essential for neuroprotection.
• CCL2 plays a novel role in endogenous neurovascular protection against stroke.