Actin polymerization and its glutathionylation are required for NET formation

Stojkov, Darko (2016). Actin polymerization and its glutathionylation are required for NET formation (Submitted). (Dissertation, Institute of Pharmacology, Faculty of Medicine of the University of Bern)

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Neutrophils are the most abundant cells in blood and their antimicrobial defense capabilities are defined, at least partially, by their formation of neutrophil extracellular traps (NETs). For the past decade, efforts have been made to elucidate the molecular mechanisms of NET formation. In this study, we demonstrate that disruption of the cellular cytoskeleton in neutrophils using pharmacological inhibitors or in knockout mice having defects in genes regulating the actin network prevents the DNA release and degranulation required for NET formation. For instance, Wiskott–Aldrich syndrome protein (WASP)deficient mouse (Was-/-) neutrophils, unable to polymerize actin, were consequently unable to release DNA or to degranulate. Furthermore, activation of mouse and human neutrophils exhibiting a genetic defect of the NADPH oxidase also failed to cause actin polymerization and subsequent NET formation. Finally, activated glutaredoxin 1 (Grx1) – deficient mouse (Grx1-/-) neutrophils accumulated high levels of glutathionylated actin that prevented actin polymerization, DNA release and degranulation. Taken together, we conclude that a functional actin network is achieved by a balance between ROS-mediated polymerization and glutathionylation and Grx1-mediated de-glutathionylation that is required for NET formation. Thus, these findings enlighten us about the molecular mechanisms involved in NET formation and provide new strategies for increasing the anti-microbial activity of neutrophils in patients with defects in the innate immune system

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