By unraveling chromatin, two enzymes help neutrophils deploy defensive webs known as NETs, Papayannopoulos et al. reveal.

NETs (neutrophil extracellular traps) not only snare invaders, they are festooned with pathogen-killing proteins, including histones, which are best known for packaging chromatin but also serve as powerful antimicrobial agents. To make a NET, a neutrophil needs to unfurl and jettison its chromatin. The cell starts by cranking up its production of reactive oxygen species, but how this surge leads to chromatin unraveling remains murky.

Neutrophils are difficult to study because they live for only about six hours. So the researchers created a cell-free system that includes neutrophil nuclei and dollops of cytoplasm from the cells. They found that two enzymes stashed in cytoplasmic granules enter the nucleus and join forces to unwind the chromatin. The first to make the move is neutrophil elastase (NE), which promotes chromosome decondensation by breaking down the H1 and H4 histones. Later in the process, myeloperoxidase (MPO) arrives at the nucleus to help NE unravel the chromatin. Exactly how MPO performs its task remains unclear, as its enzyme activity isn't required to decondense chromatin.

The researchers confirmed NE's importance for NET formation by exposing mice to Klebsiella pneumoniae bacteria. Neutrophils hustled to the lungs in control mice and in animals lacking NE. But neutrophils from the mice missing NE couldn't produce NETs to snare the bugs.

An important question to answer now, the researchers say, is how NE and MPO travel to the nucleus. The granules could merge with the nuclear membrane or burst and free the enzymes into the cytoplasm, from where they subsequently move to the nucleus.

et al
J. Cell Biol.