FIG. 3.

ROS stimulate NETosis. ROS in the neutrophil stimulate NETosis through both the NOX-dependent and NOX-independent pathways. Through the NOX-dependent pathway, ROS allow for the leakage of NE from azurophilic granules. Free from the granule, NE is free to cleave GSDM into its active form. Active GSDM forms pores in the azurophilic granules, releasing the contents into the cytosol, including NE. NE then migrates to the nuclease and degrades histones. ROS and S100A8/A9 indirectly stimulate NOX-independent NETosis through activating PAD4 through NF-κB. ROS also increase intracellular calcium, which also activates PAD4. PAD4 citrullinates arginine residues on histone tails, causing loosened DNA binding. Both pathways lead to chromatin decondensation and eventual NETosis. GSDM, gasdermin; NE, neutrophil elastase; PAD4, peptidyl arginine deiminase 4. Color images are available online.