Casting NETs for microbes

Even death doesn't stop a neutrophil from battling pathogens, as Fuchs et al. report on page 231. The infection-fighting cells often launch a neutrophil extracellular trap (NET), a mesh of DNA and enzymes that snares and kills bacteria and fungi. The authors show that NET release involves a unique type of cellular self-sacrifice and depends on reactive oxygen species (ROS).

The standard way for neutrophils to kill microbes is by devouring them. The scientists first described the cells' alternative mechanism for slaying pathogens in 2004. NETs crop up in infections such as appendicitis and pneumonia.

Now, the researchers have determined that cells perish while releasing NETs, but that NET formation differs from other types of cell death such as apoptosis or programmed cell suicide. In NET-making cells but not apoptotic cells, the nuclear membrane rips open, the contents of the nucleus and cytoplasm mingle, and the organelles vanish. Furthermore, the DNA of cells undergoing apoptosis breaks up, an event that doesn't occur in cells fashioning the microbial traps. NET formation is also distinct from necrosis spurred by bacterial toxins, the scientists showed.

Neutrophils manufacture ROS that help them demolish pathogens they have swallowed. To evaluate whether ROS help stimulate NETs, the team quenched ROS by exposing neutrophils to either an inhibitor of the ROS-producing enzyme NADPH oxidase or an enzyme that neutralizes ROS. In both cases the cells couldn't make NETs. The results might explain some of the symptoms of a rare and lethal immune disorder called chronic granulomatous disease, in which patients lack NADPH oxidase. Scientists have traditionally ascribed the patients' weak immune defenses to their neutrophils' inability to make ROS that directly destroys pathogens. But Fuchs et al. discovered that the patients also can't spin NETs.