Cathepsin D leaks out of the punctured membranes (arrows) of a granule and triggers neutrophil apoptosis.

Neutrophils that ingest bacteria die after killing their prey, thereby reining in their inflammatory effects. The authors wondered whether neutrophil granules, which are loaded with enzymes and chemicals that kill the bacteria, also kill the neutrophils.

Conus et al. now find that granules release cathepsin D, a protease known to cause nonapoptotic death in other cell types. In neutrophils, however, cathepsin D activated an apoptotic cascade by cleaving caspase-8. Because cathepsin D is only active in acidic environments, how it snips caspase-8 in the neutral cytosolic pH is unclear. Perhaps the spilling of the acidic contents of the granules lowers the pH nearby.

The granules released cathepsin D when their membranes were punctured by reactive oxygen species (ROS)—inflammatory byproducts that gradually build up in cells. Neutrophils from humans who lack an ROS-generating enzyme therefore lived longer.

Neutrophils from patients suffering from sepsis—a prolonged system-wide inflammation—also lived longer than normal neutrophils. Their granules were kept intact by neutrophil survival cytokines, which are produced during inflammation, until ROS levels rose high enough to supersede the cytokine effects. What skews the balance between these cytokines and ROS in septic patients is not known, but the development of therapies that artificially rupture the granules might help speed their recovery.