Abstract
Neutrophil extracellular traps (NETs) comprise neutrophil DNA, citrullinated (deiminated) histones, and proteases (1, 2). NET formation in vivo mostly occurs at the sites of inflammation. Neutrophils, adhering to the endothelium or after extravasation, generate NETs upon interaction with microbes, activated platelets, cytokines, alarmins, such as high-mobility group box 1 (HMGB1), or uric acid. Environmental cues, such as hyperosmolarity or hyperglycemia, neurotransmitters, and some autoantibodies also trigger NET generation (3–7). In vitro, two main pathways are activated: suicidal and vital NETosis (8). In the former, membrane integrity is disrupted and neutrophils die. In contrast, after “vital” NETosis neutrophils still migrate, chase bacteria, and extrude residual nuclear material through exocytosis (9). Generation of reactive oxygen species (ROS) and fusion of neutrophil primary granules with the nuclear membrane that promote interactions between elastase, myeloperoxidase (MPO), and DNA are features of suicidal NETosis. Their role in vital NETosis is debated (8, 10–12). Activation of the autophagic pathway is intermingled with NET generation. Autophagy sustains the metabolic requirements of the extensive intracellular vesicular formation, transport, and fusion associated with NET generation. It also sustains neutrophil survival (5).
Highlights
Neutrophil extracellular traps (NETs) comprise neutrophil DNA, citrullinated histones, and proteases [1, 2]
Activation of the autophagic pathway is intermingled with NET generation
Some reports indicate a role of the mitochondrial DNA, which is devoid of histones, in NET generation
Summary
Generation of reactive oxygen species (ROS) and fusion of neutrophil primary granules with the nuclear membrane that promote interactions between elastase, myeloperoxidase (MPO), and DNA are features of suicidal NETosis. Their role in vital NETosis is debated [8, 10,11,12]. The actions of NET-embedded von Willebrand factor, of citrullinated histones, and of negative charges on platelet recruitment/activation and on the progression of the coagulation cascade contribute to thrombosis Excellent reviews on this issue have been published [16, 17].
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