MPO Negatively Regulates Neutrophil-EC Interactions By Impairing αMß2 Integrin in Sterile Inflammation

Interactions between neutrophils with platelets and endothelial cells (ECs) contribute to vascular occlusion and tissue damage in sterile inflammatory conditions. However, the molecular mechanisms underlying the cell-cell interactions are not fully understood. Previous studies show that reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), modulate neutrophil αMβ2 integrin function and play a role in mediating platelet-neutrophil heterotypic interactions. In this study, we further characterize a role for myeloperoxidase (MPO) in regulating neutrophil adhesive function through αMβ2 integrin. Using real-time fluorescence intravital microscopy and in vitro assays, we found that loss of MPO enhanced neutrophil-EC interactions and subsequent neutrophil transmigration under inflammatory conditions but did not affect neutrophil-platelet interactions. Using both genetic and pharmacologic approaches, we showed that following activation, MPO KO neutrophils had enhanced extracellular H2O2 production and increased surface level of αMβ2 integrin and that these effects were dependent on MPO activity. Our in vivo studies using a hepatic ischemia/reperfusion-induced inflammation model found that compared to WT mice, neutrophils from MPO KO mice had a pro-migratory phenotype while tissue damage was reduced. These results indicate that under sterile inflammatory conditions, MPO plays a negative role in the adhesive and migratory function of neutrophils by diminishing αMβ2 integrin function.