Pathological Effects of NETs: Seed and soil hypothesis for inflammation spread by primed neutrophils

The ability of activated neutrophils to release decondensed chromatin as neutrophil extracellular traps (NETs) in response to stimuli is conserved throughout evolution. While NETs support host defense by forming physical barriers against microbes, their toxicity can cause tissue damage. Large NET networks, generated through the activation of the NLRP3 inflammasome, the citrullinating enzyme PAD4, and neutrophil-derived enzymes, are central to the pathogenesis of numerous diseases. Chronic disorders often originate in a localized site, for example the joints in rheumatoid arthritis, or following a major inflammatory event, before progressing to distant organs, such as the heart. In this perspective, we hypothesize that circulating primed neutrophils represent the "seeds" of chronic disease, that adhere to activated vessels, the "soil" of susceptible organs. We explore the mechanisms underlying NET formation and discuss animal and human evidence supporting our hypothesis.