OUR RESEARCH

WT

PDI CKO

The mechanisms regulating platelet activation and aggregation in arterial thrombosis

Arterial thrombotic diseases, including coronary/peripheral artery diseases and stroke, are the number one killer in the U.S. Underlying these pathologies is increased platelet activity. Mounting evidence indicates that oxidation or reduction of allosteric disulfide bonds induces a conformational change(s) in plasma proteins and cell surface molecules and alters their functions. Thiol isomerases, such as protein disulfide isomerase (PDI), are responsible for modifying allosteric disulfide bonds. We have demonstrated that platelet-released PDI directly interacts with cell surface molecules, such as β3 integrin and glycoprotein Ibα (GPIbα), during cell activation and promotes platelet adhesive function in arterial thrombosis and thromboinflammation (Kim et al. Blood 2013; Li et al. Circulation 2019). We are identifying platelet surface receptors whose function is regulated by thiol isomerases and how the activities of PDI and other thiol isomerases are controlled in thrombosis.

Anucleate platelets can synthesize proteins using mRNAs and microRNAs under disease conditions. Intriguingly, platelets contain transcriptional regulators. We have demonstrated that the mRNA and protein of downstream regulatory element antagonist modulator (DREAM, a transcriptional repressor) are present in platelets and that platelet DREAM promotes the activity of phosphoinositide-3-kinase during platelet activation and arterial thrombosis (Kim et al. Blood 2017). These results indicate the possibility of non-transcriptional roles of transcriptional regulators in platelet function. We are identifying the novel signaling pathways modulated by transcription factors and repressors that may affect platelet function in arterial thrombosis.

The mechanisms regulating neutrophil activation and recruitment in vascular inflammation

Neutrophils are essential for innate immunity, yet excessive recruitment to sites of inflammation causes severe tissue damage. Furthermore, adherent neutrophils support adhesion of other blood cells, such as platelets and red blood cells, leading to cell-cell aggregation and vascular occlusion. We showed that neutrophil PDI directly binds to αMβ2 integrin and enhances its ligand-binding function, promoting neutrophil recruitment to sites of inflammation (Hahm et al. Blood 2013). Importantly, we have demonstrated that AKT2 and NOX2 signaling promotes the ligand-binding function of neutrophil αMβ2 integrin, increasing neutrophil adhesive function in vascular inflammation (Li et al. J Clin Invest 2014; Kim et al. Blood 2015; Kim et al. Haematologica 2017). In our recent study, we have found that neutrophil DREAM positively regulates neutrophil adhesive function in NF-κB-dependent and independent manners. We are investigating the novel mechanisms regulating the interactions of neutrophils with inflamed endothelial cells.

WT

PDI CKO

The mechanisms regulating platelet-neutrophil interactions under thromboinflammatory conditions

Thrombosis and inflammation occur concurrently or sequentially, activating a vicious cycle that exacerbates the pathological conditions. Thromboinflammation-related diseases, including ischemic stroke, acute lung injury and peripheral vasculitis, result in >30% of all deaths globally. Platelets, leukocytes and coagulation cascades play central roles in mediating thromboinflammation. In particular, activated platelets and neutrophils interact under the disease condition and release pro-thrombotic and pro-inflammatory molecules, aggravating the pathology. The heterotypic platelet-neutrophil interaction is mediated mainly by the interactions of platelet P-selectin and glycoprotein Ibα with neutrophil PSGL-1 and αMβ2 integrin, respectively. We have identified several signaling pathways that play crucial roles in regulating the ligand-binding function of the cell surface molecules under thromboinflammatory conditions, including sickle cell disease and ischemia/reperfusion-induced tissue injury (Li et al. J Clin Invest 2014; Kim et al. Blood 2015; Li et al. Circulation 2019; Li et al. J Exp Med In press). We are investigating the key mechanisms mediating platelet-neutrophil aggregation, which could pave the way to developing a novel therapeutic strategy.