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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL109439-05
Application #
8899366
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Charette, Marc F
Project Start
2011-09-01
Project End
2017-07-31
Budget Start
2015-08-01
Budget End
2017-07-31
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Li, Jing; Cho, Jaehyung (2017) Ser/Thr protein kinase B?-NADPH oxidase 2 signaling in thromboinflammation. Curr Opin Hematol 24:460-466
Cho, Jaehyung (2017) Downstream Regulatory Element Antagonist Modulator (DREAM), a target for anti-thrombotic agents. Pharmacol Res 117:283-287
Kim, Kyungho; Tseng, Alan; Barazia, Andrew et al. (2017) DREAM plays an important role in platelet activation and thrombogenesis. Blood 129:209-225
Kim, Kyungho; Li, Jing; Barazia, Andrew et al. (2017) ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease. Haematologica 102:246-259
Delaney, M Keegan; Kim, Kyungho; Estevez, Brian et al. (2016) Differential Roles of the NADPH-Oxidase 1 and 2 in Platelet Activation and Thrombosis. Arterioscler Thromb Vasc Biol 36:846-54
Estevez, Brian; Kim, Kyungho; Delaney, M Keegan et al. (2016) Signaling-mediated cooperativity between glycoprotein Ib-IX and protease-activated receptors in thrombin-induced platelet activation. Blood 127:626-36
Huang, Xiaojia; Dai, Zhiyu; Cai, Lei et al. (2016) Endothelial p110?PI3K Mediates Endothelial Regeneration and Vascular Repair After Inflammatory Vascular Injury. Circulation 133:1093-103
Kim, Kyungho; Li, Jing; Tseng, Alan et al. (2015) NOX2 is critical for heterotypic neutrophil-platelet interactions during vascular inflammation. Blood 126:1952-64
Barazia, Andrew; Li, Jing; Kim, Kyungho et al. (2015) Hydroxyurea with AKT2 inhibition decreases vaso-occlusive events in sickle cell disease mice. Blood 126:2511-7
Li, Jing; Kim, Kyungho; Barazia, Andrew et al. (2015) Platelet-neutrophil interactions under thromboinflammatory conditions. Cell Mol Life Sci 72:2627-43

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