Fig. 1

Activating stimuli and molecules involved in the two types of NETosis: lytic NETosis (left) consists in a mechanism that effectively kills neutrophils, which by breaking down releases the filamentous lattice made of decondensed chromatin, histones, and lytic enzymes into the extracellular space. Known activators of lytic/suicidal NETosis are PMA (Phorbol 12-myristate 13-acetate) and antibodies through binding to the Fc receptor; extracellular signals lead to calcium-dependent activation of NADPH oxidase and release of reactive oxygen species (ROS). ROS cause the activation of the PAD4 enzyme and translocation from granules to the nucleus of Neutrophil Elastase (NE) and Myeloperoxidase (MPO); combined action of PAD4, NE, and MPO results in citrullination of histones, in particular H3, and subsequent chromatin decondensation. The nuclear membrane of neutrophils breaks, and the chromatin mixed with enzymes and histones is released first into the cytoplasm and then into the extracellular space, following the rupture of the cell membrane, forming Neutrophil Extracellular Traps (NETs). In vital NETosis (right), the neutrophil remains intact releasing the reticulum via a system of vesicles; the latter mechanism appears to be independent of NADPH oxidase activation. Microbial infections, especially from S. aureus, recognized by Toll-Like Receptor-2 (TLR2) or Complement Receptor and LPS-activated platelets that bind Toll-Like Receptor-4 are among the major proven activators of this second pathway