Cell Death and Destruction

Upon contact with their bacterial targets, neutrophils fire a barrage of antimicrobial peptides, sometimes releasing structures called neutrophil-associated extracellular traps, or NETs. In releasing their NETs, they commit suicide—unleashing their entire antibacterial arsenal via a specialized form of programmed cell death called netosis. Hakkim et al. (2011) now provide new insight into the molecular triggers for netosis. The authors first employ a high-throughput approach to rapidly and quantitatively examine the cellular changes that accompany NET formation in isolated human neutrophils. They then screen for small molecules that inhibit or delay netosis, isolating two classes of compounds that block NET formation. One includes chemicals that block the production of reactive oxygen species (ROS), which have been implicated in netosis, and one contains molecules that are known to inhibit transduction through the Raf-MEK-ERK signaling cascade. The authors go on to dissect how this pathway influences NET formation by challenging neutrophils with either proinflammatory lipids or Helicobacter pylori, the stomach bacterium that causes ulcers. Despite some differences, all stimuli cause netosis by elevating production of ROS by stimulation of NADPH oxidase via the Raf-MEK-ERK pathway. Though NET formation can be beneficial, excessive netosis is associated with a variety of autoimmune diseases, and this new understanding of the molecular player that is responsible for netosis could provide a foothold for an assault on excessive innate immune responses. Hakkim, A., et al. (2011). Nat. Chem. Biol. 7, 75–77.