Fig. 1

Two types of process of NETosis: Suicidal NETosis (A-C) vs vital NETosis (D-F). A Various substances, including PMA and cytokines, can induce suicidal NETosis. Subsequent increases in cytoplasmic calcium activate PKC or Raf/MEK/ERK kinase pathways, which in turn activate niacinamide adenine dinucleotide phosphate (NADPH) oxidase complexes (NOX) and subsequent reactive oxygen species (ROS) production. B Peptidyl arginine deiminase-4 (PAD4), together with neutrophil elastase (NE) and myeloperoxidase (MPO), induces histone H3 citcitylation (CitH3), which further leads to decondensation of chromatin and loss of the lobular shape of the nucleus. Subsequently, nuclear envelope rupture and chromatin expansion into the cytoplasm. C Plasma membrane rupture and NET release. D In contrast, vital NETosis can be stimulated by activated platelets (PLTs), microorganisms, and complement proteins. And then, toll-like receptors (TLR) 2 and TLR 4 can be activated, leading to the activation of PAD4. Small conductance potassium channel member 3 (SK3) activated by calcium is also involved in the regulation. E Decondensation of chromatin and loss of the lobular shape of the nucleus. The external and internal nuclear membranes are then separated and the vesicles sprout. F NETs are sent out of the neutrophil by vesicles. This process protects the outer membrane of the neutrophils, thus allowing them to continue to function, even to the point of becoming anuclear