AUTHOR=Tseng Alan , Kim Kyungho , Li Jing , Cho Jaehyung 

TITLE=Myeloperoxidase Negatively Regulates Neutrophil–Endothelial Cell Interactions by Impairing αMβ2 Integrin Function in Sterile Inflammation

JOURNAL=Frontiers in Medicine

VOLUME=Volume 5 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2018.00134

DOI=10.3389/fmed.2018.00134

ISSN=2296-858X

ABSTRACT=Interactions of neutrophils with endothelial cells and platelets contribute to tissue damage and vascular occlusion under sterile inflammatory conditions. However, the molecular mechanisms regulating the cell-cell interactions remain poorly understood. Previous studies suggest that reactive oxygen species (ROS), such as H2O2, produced from NADPH oxidase 2 play a critical role in platelet-neutrophil interactions by regulating the function of neutrophil αMβ2 integrin during sterile inflammation. In this study, we further demonstrate a crucial role for myeloperoxidase (MPO) in regulating the adhesive function of neutrophils through αMβ2 integrin. Using real-time fluorescence intravital microscopy and in vitro assays, we showed that loss of MPO promoted neutrophil-endothelial cell interactions and neutrophil emigration but did not affect neutrophil-platelet interactions under inflammatory conditions. Using genetic and pharmacologic approaches, we found that following agonist stimulation, MPO knockout (KO) neutrophils exhibited a significant increase in extracellular hydrogen peroxide (H2O2) and surface level of αMβ2 integrin and that these effects were dependent on MPO activity. Our in vivo studies using an ischemia/reperfusion-induced hepatic inflammation model revealed that compared to WT mice, MPO KO neutrophils displayed a pro-migratory phenotype while ameliorating tissue damage. These results suggest that MPO plays a negative role in the adhesive and migratory function of neutrophils by impairing αMβ2 integrin function under sterile inflammatory conditions.