Fig. 2: Illustrative representation of the neutrophil extracellular trap (NET) formation and degradation cascade.

1. Neutrophils, via a trans-endothelial mechanism, are recruited to the site of an incident within hours. There they form NETs by releasing nuclear chromatin or mitochondrial DNA decorated with potent antimicrobial granular proteins. 2. Monocyte and activated macrophages secrete neutrophil chemoattractants that lead to a rapid influx of a large number of neutrophils. At these high densities, neutrophils aggregate, forming so-called aggregated NETs (aggNETs). These foster the resolution of inflammation by degrading small soluble mediators of inflammation. 3. Within days to weeks, after NETs enabled a successful entrapment of pathogens and restricted their dissemination, intracellular DNases break down the DNA backbone of NETs. These remnants can then be cleared by phagocytic cells (e.g., macrophages) to promote clearance and thereby restore homeostasis. 4. Ineffective clearance of NETs leads to their extended and prolonged ripening by forming stable aggNET-fibrin co-aggregates, in which fibrin polymerizes in the scaffold formed by NETs. In these aggregates fibrin can be citrullinated and, consequently, resists degradation by plasmin. In addition, the NETs incorporated in these aggregates were protected from DNases. A reduced clearance then may lead to long-term secondary inflammation and formation of stones and tophi.