Abstract
Neutrophil extracellular traps (NETs) are one of the most intriguing discoveries in immunological research of the past few years. After their first description in 2004, the number of research articles on how NETs affect immunodefense, and also how they contribute to an ever-growing number of diseases, has skyrocketed. However, tempting as it may seem to plunge into pharmaceutical approaches to tamper with NET formation, our understanding of this complex process is still incomplete. Important concepts such as the context-dependent dual functions of NETs, in that they are both inflammatory and anti-inflammatory, or the major intra- and extracellular forces driving NET formation, are only emerging. In this Review, we summarize key aspects of our current understanding of NET formation (also termed NETosis), emphasize biophysical aspects and focus on three key principles - rearrangement and destabilization of the plasma membrane and the cytoskeleton, alterations and disassembly of the nuclear envelope, and chromatin decondensation as a driving force of intracellular reorganization.
Highlights
To protect themselves from intruding pathogens, many species have developed complex mechanisms of immune defense
From a clinical point of view, understanding the processes underlying neutrophil extracellular traps (NETs) formation is of fundamental importance (Fig. 6), as aberrant NET formation appears to be a key factor in the pathogenesis of a number of diseases, most prominently autoimmune diseases and cardiovascular disease, including myocardial infarction, as well as cancer growth and metastasis
At later time points, when the cell has entered the passive phase of NET formation, this active inhibition has proven to be unsuccessful
Summary
To protect themselves from intruding pathogens, many species have developed complex mechanisms of immune defense. Setting the stage – increasing cellular vulnerability From a biomechanical and/or biophysical point of view, the formation of NETs involves dramatic rearrangements of the cellular and nuclear content, from chromatin decondensation and cell membrane reorganization to the degradation of the cytoskeleton and the disassembly of the nuclear envelope, and final release of the NET through the plasma membrane These processes are explained in more detail below. During the first active phase of NET formation, cells become substantially softer, and their membrane (tether) tension greatly decreases over time, indicating the destabilization of the actin cytoskeleton (Neubert et al, 2018) In this context, it is important to mention that other cell organelles within the neutrophilic cytoplasm disappear in the early stages of NET formation. PMA-induced NET formation does not require adhesion, as shown by experiments on passivated surfaces (Erpenbeck et al, 2019), while for LPSinduced NET formation it is essential (Erpenbeck et al, 2019)
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