Targeting Neutrophil α9 Improves Functional Outcomes After Stroke in Mice With Obesity-Induced Hyperglycemia

Area of Science:

• Immunology
• Neurology
• Cardiovascular Research

Background:

• Obesity-induced hyperglycemia is a major stroke risk factor.
• Integrin α9β1 on neutrophils mediates endothelial adhesion.
• The specific role of neutrophil-derived α9 in stroke is not fully understood.

Purpose of the Study:

• To investigate the role of neutrophil-specific α9 in stroke outcomes in a mouse model of obesity-induced hyperglycemia.
• To determine if targeting neutrophil α9 can mitigate stroke-related damage and improve functional recovery.

Main Methods:

• Obesity and hyperglycemia were induced in mice using a high-fat diet.
• Neutrophil-specific α9 knockout mice (α9^Neu-KO) and controls (α9^WT) underwent transient middle cerebral artery ischemia.
• Infarct volume, cerebral blood flow, thrombo-inflammation markers, neutrophil extracellular trap formation (NETosis), and functional outcomes were assessed.

Main Results:

• Neutrophil α9 expression was upregulated in obese mice post-stroke.
• Deletion of neutrophil α9 improved functional outcomes, reduced infarct size, and decreased thrombo-inflammation and NETosis.
• The α9/cellular fibronectin-EDA axis was identified as a key mechanism contributing to NETosis and worsened stroke outcomes.

Conclusions:

• Genetic deletion or pharmacological inhibition of neutrophil-specific α9 significantly improves long-term functional outcomes after stroke in obese, hyperglycemic mice.
• These improvements are primarily attributed to the limitation of post-stroke thrombo-inflammation and NETosis.
• Neutrophil α9 represents a promising therapeutic target for stroke in the context of metabolic disorders.