How Do ROS Induce NETosis? Oxidative DNA Damage, DNA Repair, and Chromatin Decondensation

Neutrophil extracellular traps (NETs) are intricate, DNA-based, web-like structures adorned with cytotoxic proteins. They play a crucial role in antimicrobial defense but are also implicated in autoimmune diseases and tissue injury. The process of NET formation, known as NETosis, is a regulated cell death mechanism that involves the release of these structures and is unique to neutrophils. NETosis is heavily dependent on the production of reactive oxygen species (ROS), which can be generated either through NADPH oxidase (NOX) or mitochondrial pathways, leading to NOX-dependent or NOX-independent NETosis, respectively. Recent research has revealed an intricate interplay between ROS production, DNA repair, and NET formation in different contexts. UV radiation can trigger a combined process of NETosis and apoptosis, known as apoNETosis, driven by mitochondrial ROS and DNA repair. Similarly, in calcium ionophore-induced NETosis, both ROS and DNA repair are key components, but only play a partial role. In the case of bacterial infections, the early stages of DNA repair are pivotal. Interestingly, in serum-free conditions, spontaneous NETosis occurs through NOX-derived ROS, with early-stage DNA repair inhibition halting the process, while late-stage inhibition increases it. The intricate balance between DNA repair processes and ROS production appears to be a critical factor in regulating NET formation, with different pathways being activated depending on the nature of the stimulus. These findings not only deepen our understanding of the mechanisms behind NETosis but also suggest potential therapeutic targets for conditions where NETs contribute to disease pathology.