Neutrophil Extracellular Traps

Neutrophil extracellular traps (NETs) were first described in 2004 by Volker Brinkmann at the Max Planck Institute for Infection Biology (Brinkmann V et al. 2004). Evolutionarily, this molecular reaction mechanism is designed to kill invading pathogens or to limit their spread and preserve the integrity and functionality of tissues.

Neutrophil extracellular traps, or NETs for short, are networks of cell-free DNA and proteins that are ejected by activated neutrophil granulocytes. They are capable of trapping pathogens, attacking them with antimicrobial proteins such as elastase and cathepsin G and at the same time activating the immune system. Granulocytes use NETs to attack pathogenic microorganisms. The process of activation and release of NETs is abbreviated as NETosis.

Neutrophil granulocytes are cells of the innate immune system. If pathogens enter our body, neutrophil granulocytes can identify them and render them harmless. To do this, "neutrophils" have various defense mechanisms at their disposal - they can absorb and digest pathogens or release antimicrobial toxins. The so-called"neutrophil extracellular traps", or NETs for short, form a third defense mechanism: when neutrophils come into contact with pathogens, they can dissolve their cell and nuclear membrane and "eject" net-like DNA structures. The pathogens stick to these DNA network structures (DNA traps) and are killed by the simultaneous release of antimicrobial substances.

The remaining bacterial DNA is then disposed of by macrophages. These take up the DNA residues in their phagosome, a closed cell compartment that can digest cell residues. Apparently, however, NETs are also translocated into the cell interior. Here they are recognized by CGAS, a cyclic GMP-AMP synthase (Apel F et al.). This reactivity triggers the production of type I interferons and activates the immune system, which in turn recruits further immune cells.

Remark: Not only bacterial DNA but also IgA and IgG immune complexes are strong triggers for the formation of NETs. For example, neutrophil granulocytes express IgA- and IgG-specific Fc receptors (FcRs) and therefore respond to complexed IgA and IgG (Aleyd E et al. 2014). While the stimulation of neutrophil granulocytes with IgA complexes strongly induces the formation of NETs, complexed IgG only slightly increases the number of NETs. IgA could therefore be the most important driving force in (auto)immune complex-mediated NETosis (Gimpel AK et al. 2022).

NETs play a pathophysiological role in IgA vasculitis. NETs have been shown to enter the circulation in IgA vasculitis and play an important role in the activity of the disease. The circulating quantities of NETs correlate strongly with the severity of the vasculitis (Chen XQ et al. 2021). The NETs released by activation of the IgA-Fc receptor (FcaRI) can lead to increased TNF-alpha production. The opposite is achieved by blocking the IgA-Fc receptor (Aleyd E et al. 2014). The blockade inhibits phagocytosis and the formation of NETs.

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