Bet on NETs! Or on How to Translate Basic Science into Clinical Practice

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). Neutrophils undergo extensive ex vivo manipulations and methodological approaches vary among research groups, possibly explaining some discrepancies and nurturing some healthy skepticism (13). Some reports indicate a role of the mitochondrial DNA, which is devoid of histones, in NET generation. The relative contribution of nuclear vs. mitochondrial DNA to extracellular traps generation remains a controversial issue (14). Under physiological conditions, NETs enhance the host response to microbes by (i) providing a template concentrating humoral innate immune molecules, such as pentraxin 3 (PTX3) and complement, together with microbicidal molecules, such as histones, MPO, proteinase 3 (PR3), or cathelicidin, and (ii) contrasting the hematogenic spread of pathogens through immunothrombosis (i.e., activation of platelets and of the coagulation cascade through NET components) (15). 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). The bioactive molecules integrated within the chromatin threads may vary according to the inciting stimuli or the environment. The characterization of the NETs proteome is a fascinating challenge for the near future. Neutrophils are abundant in the blood, and their concentration and activation state increase following surges of systemic cytokines during acute phase responses. Thus, NETs are readily …