Neutrophil extracellular traps (NETs) represent an important defense mechanism 
against microorganisms. Clearance of NETs is impaired in a subset of patients 
with systemic lupus erythematosus, and NETosis is increased in neutrophils and, 
particularly, in low-density granulocytes derived from lupus patients. NETs are 
toxic to the endothelium, expose immunostimulatory molecules, activate 
plasmacytoid dendritic cells, and may participate in organ damage through 
incompletely characterized pathways. To better understand the role of NETs in 
fostering dysregulated inflammation, we examined inflammasome activation in 
response to NETs or to LL-37, an antibacterial protein externalized on NETs. 
Both NETs and LL-37 activate caspase-1, the central enzyme of the inflammasome, 
in both human and murine macrophages, resulting in release of active IL-1β and 
IL-18. LL-37 activation of the NLRP3 inflammasome utilizes P2X7 
receptor-mediated potassium efflux. NET and LL-37-mediated activation of the 
inflammasome is enhanced in macrophages derived from lupus patients. In turn, 
IL-18 is able to stimulate NETosis in human neutrophils. These results suggest 
that enhanced formation of NETs in lupus patients can lead to increased 
inflammasome activation in adjacent macrophages. This leads to release of 
inflammatory cytokines that further stimulate NETosis, resulting in a 
feed-forward inflammatory loop that could potentially lead to disease flares 
and/or organ damage.