Neutrophils are essential for the innate immune response during vascular inflammation and injury. Neutrophil recruitment into the site of vascular injury is a multi-step process consisting of neutrophil rolling, firm adhesion, and transmigration. Interaction of selectins with their ligands mediates neutrophil rolling over the inflamed endothelium and further regulates integrin function. Subsequently, activated LFA-1 and Mac-1 play critical roles in neutrophil adhesion to and transmigration across the endothelium. However, the molecular mechanism by which the integrins are activated during neutrophil recruitment remains unclear. It has been proposed that redox-sensitive thiol-disulfide exchange in integrins may be important for their activation. Protein disulfide isomerase (PDI), a cell surface localized thiol isomerase, plays an important role in thiol exchange in b3 integrins, thereby regulating b3 integrin-mediated platelet and endothelial cell function. It is our hypothesis that neutrophil surface PDI regulates b2 integrin function by facilitating redox-sensitive thiol exchange, shifting b2 integrin to its active conformation required for b2 integrin-mediated neutrophil recruitment during inflammation. Based on our preliminary data which strongly support the hypothesis, in Aim 1, we will define the role of cell surface PDI in the interaction of b2 integrin with its counter-receptor, ICAM-1 and in b2 integrin-mediated neutrophil adhesion and transmigration.
In Aim 2, we will identify the molecular mechanisms by which PDI interacts with b2 integrins to regulate their function.
In Aim 3, we will investigate the pathophysiological role of cell surface PDI in b2 integrin-mediated neutrophil adhesion and transmigration under inflammatory conditions using real-time fluorescence intravital microscopy in vivo. A better understanding of how surface PDI regulates b2 integrin-mediated neutrophil recruitment into the site of inflammation may lead to the development of novel therapeutics to prevent and treat inflammation and tissue injury.
Acute inflammation leads to high mortality and morbidity in the U.S. The proposed studies will help determine how circulating neutrophils recruit into the site of inflammation. Integrins (cell surface receptors) are necessary for neutrophil recruitment during inflammation. Therefore, molecules such as PDI which can regulate integrin function could be a novel target to prevent and treat inflammation.
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