Suicidal NETosis vs vital NETosis. (A-C) Suicidal NETosis classically occurs following stimulation by PMA through activation of protein kinase C and the raf–mitogen-activated protein kinase (MEK)–extracellular signal-regulated kinase (ERK) pathway. NADPH assists in the translocation of neutrophil elastase from cytosolic granules into the nucleus where it aids in chromatin breakdown via histone cleavage. MPO is required for chromatin and nuclear envelope breakdown and granular mixing within the NET vacuole. Following 120 minutes of intracellular NET formation, the neutrophil outer membrane ruptures, and the mature NET is extruded. (D-F) By contrast, vital NETosis has been reported following both direct microbial exposure and lipopolysaccharide (LPS). Live S aureus induce rapid NET release (<30 minutes) in human and mouse neutrophils in vitro and in vivo. For gram-negative bacteria, NETs are induced via Toll-like receptor (TLR) 4 activation of platelets followed by direct neutrophil-platelet interaction via CD11a, whereas both complement receptor 3 and TLR2 are required for vital NETosis following gram-positive infection. NETs are released via nuclear budding (G-H) and vesicular release of NETs (I). This mechanism spares the PMN outer membrane, thereby allowing the PMN to continue to function, even to the point of becoming anuclear. (Panels G-I were reproduced from Pilsczek et al14 with permission (© 2010 by The American Association of Immunologists).
