To the editor:Akt is essential to induce NADPH-dependent NETosis and to switch the neutrophil death to apoptosis

摘要

Neutrophil extracellular traps (NETs) have been recently identified as major contributors of several hematological and vascular diseases. These disorders include thrombosis, small vessel vasculitis, systemic lupus erythematosus, autoimmunity, pneumonia, sepsis, and blood transfusion-related acute lung injury.1^ NETs are DNA-based extracellular traps that not only trap and kill invading microbes but also injure host tissues.1'5"7 Therefore, regulating NETosis is important to prevent many pathological conditions.1 However, key molecules that switch neutrophil death from NETosis, which is proinfiam-matory, to apoptosis, which is anti-inflammatory, have not been clearly established.Nicotinamide adenine dinucleotide phosphate oxidase 2 (N0X2)-dependent reactive oxygen species (ROS) production in neutrophils can induce either NETosis or apoptosis. Phorbol 12-myristate 13-acetate (PMA) has been extensively used as an agonist to activate NOX2-mediated ROS production to study NETosis.6'8 A seminal study showed that PMA induces autophagy and that both autophagy and PMA-mediated ROS production are required for NETosis.8 This inference was made based on the inhibitory effect of a protein kinasae C inhibitor (wortmannin) on PMA-mediated autophagy and NETosis. In another study, rapamycin was used for directly suppressing mammalian target of rapamycin, a well-established regulator of autophagy. These studies show that mammalian target of rapamycin regulates NETosis via modifying hypoxia-inducible factor HIFl-a.9 However, the identities of other key kinases that regulate NETosis-apoptosis pathways remain elusive.