Human serum albumin modified in myeloperoxidase-dependent reactions is a mediator of neutrophil extracellular trap formation

Abstract

Abstract Activation of neutrophil membrane receptors initiates intracellular signal transduction cascades that orchestrate the cell’s effector functions, including phagocytosis, production of reactive oxygen and halogen species, degranulation, and NETosis (formation of neutrophil extracellular traps (NETs). NETs, which contain antimicrobial compounds such as myeloperoxidase (MPO), represent a strategy to combat infection. However, excessive production of NETs promotes thrombosis, diabetes mellitus, and other diseases. Therefore, investigations into the mechanisms of NETosis and the identification of modulators of this process are critical for developing strategies to address NETosis-related disorders. Here, we identified a novel NETosis inducer, human serum albumin (HSA) modified by the MPO product hypochlorous acid (HSA HOCl ), whose accumulation in vivo was correlated with inflammatory processes. Using human blood neutrophils, we investigated HSAHOCl–induced NETosis and detected NET formation by flow cytometry. The results showed that the mechanism of HSAHOCl-induced NETosis involved MPO, NADPH oxidase and phosphatidylinositol 3-kinases, and that HSAHOCl activated a reactive oxygen species-dependent suicidal type of NETosis. Moreover, HSAHOCl-induced NETosis was inhibited by an anti-HSA HOCl monoclonal antibody. Thus, our findings may facilitate the development of strategies to modulate NETosis in inflammation correlated with elevated MPO activity.

Keywords: NETosis, neutrophil extracellular traps, human serum albumin, myeloperoxidase, hypochlorous acid, reactive halogen species