SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx

Neutrophils release neutrophil extracellular traps (NETs) to combat pathogens. While beneficial against microbes, NETs also contribute to inflammatory and autoimmune diseases. This study investigates NOX-independent NETosis, a less understood form of NET release. The researchers demonstrate that calcium-activated NOX-independent NETosis is rapid and depends on the SK3 potassium channel and mitochondrial reactive oxygen species (ROS). This pathway differs from NOX-dependent NETosis in its kinase activation profile, with lower ERK and moderate Akt activation, but similar p38 activation. Importantly, Akt is crucial for both pathways, while ERK is only essential for the NOX-dependent pathway. The findings highlight key differences between these NETosis pathways and suggest potential therapeutic targets for diseases involving unregulated NETosis.

David Nobuhiro Douda, Meraj A. Khan, Hartmut Grasemann, Nades Palaniyar