Neutrophil Function in Ischemic Stroke: Insights from Protein Disulfide Isomerase Deficiency

Neutrophils are the most abundant myeloid cells and serve as frontline responders during acute inflammation.Their recruitment to inflamed vessels proceeds through a multistep cascade in which β2-integrins play a central role in mediating stable adhesion and transendothelial migration.Protein disulfide isomerase A1 (PDI, also referred to as PDIA1) is a thiol-oxidoreductase traditionally known to catalyze disulfide bond formation within the endoplasmic reticulum.However, accumulating evidence suggests that it also exerts extracellular regulatory functions by modulating integrin activation via redox-mediated thiol-disulfide exchange.In vivo studies have shown that genetic deletion or antibody blockade of PDI markedly reduces neutrophil adhesion, crawling, and transendothelial migration, underscoring its essential role in neutrophil-endothelium interactions.Notably, cerebral intravital imaging in ischemic stroke models has demonstrated that PDI inhibition attenuates neutrophil trafficking in the cerebral microvasculature.Collectively, these findings indicate that PDI functions as a fundamental regulator of β2-integrin-mediated neutrophil recruitment and represents a potential therapeutic target for mitigating neurovascular inflammation and ischemia-reperfusion injury.