Chromatin decondensation during NET formation requires histone citrullination mediated by peptidylarginine deaminase 4 (PAD4) as a prerequisite for DNA release (Neeli et al., Wang et al.). In most experimental settings, NET formation requires a functional NADPH oxidase to produce oxidants, which promote release of NE. NETs are lattice-like structures composed of nuclear DNA, histones, and at least 24 associated proteins (Urban et al.), including neutrophil granule proteins that form when neutrophils undergo cytolysis after exposure in vitro to a variety of agonists (Brinkmann et al.). To set the starting point for this dialogue, we need to introduce both the subject and the discussants. Our intention in the conversation to follow is to evaluate critically the state of the study of Neutrophil Extracellular Traps (NETs), a phenomenon currently the object of considerable interest in order to identify aspects that merit clarification and thereby to assign the process its proper place in our current understanding of cell biology. In this discussion, the authors challenge interpretation of data from some experimental settings and provide recommendations for specific studies that would address the concerns raised, improve understanding of the biological relevance of NETs, and strengthen the field. However, an overview of work in this rapidly growing field prompts several fundamental questions about NETs, both those created in vitro and those found in vivo, including their precise composition, the mechanisms by which they arise, their clinical relevance, and the interrelationship of those observed in vitro and in vivo. Since the seminal observations in the Zychlinsky laboratory that described the extrusion of filaments of nuclear DNA associated with histones and granule proteins from neutrophils stimulated in vitro, many investigators have examined the phenomenon of NET formation in numerous and diverse settings. The authors engage in a dialogue that evaluates critically the state of the study of Neutrophil Extracellular Traps (NETs), a phenomenon currently the object of considerable interest, with the goal of identifying those aspects that merit clarification in order to assign the process its proper place in our current understanding of cell biology.
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