PT  - JOURNAL ARTICLE
AU  - Sollberger, Gabriel
AU  - Choidas, Axel
AU  - Burn, Garth Lawrence
AU  - Habenberger, Peter
AU  - Di Lucrezia, Raffaella
AU  - Kordes, Susanne
AU  - Menninger, Sascha
AU  - Eickhoff, Jan
AU  - Nussbaumer, Peter
AU  - Klebl, Bert
AU  - Krüger, Renate
AU  - Herzig, Alf
AU  - Zychlinsky, Arturo
TI  - Gasdermin D plays a vital role in the generation of neutrophil extracellular traps
AID  - 10.1126/sciimmunol.aar6689
DP  - 2018 Aug 24
TA  - Science Immunology
PG  - eaar6689
VI  - 3
IP  - 26
4099  - http://immunology.sciencemag.org/content/3/26/eaar6689.short
4100  - http://immunology.sciencemag.org/content/3/26/eaar6689.full
SO  - Sci. Immunol.2018 Aug 24; 3
AB  - Gasdermin D (GSDMD), a pore-forming protein, has emerged as a key downstream effector in pyroptosis, a form of cell death induced by intracellular lipopolysaccharide (LPS). Here, Sollberger et al. demonstrate that GSDMD is activated in neutrophils, during the generation of neutrophil extracellular traps (NETs). NETs are composed of chromatin and antimicrobial proteins and are cast by dying neutrophils in a process termed NETosis. While carrying out a chemical screen to identify molecules that block NETosis, Sollberger et al. identified a pyrazolo-oxazepine scaffold–based molecule that binds GSDMD to be an inhibitor of NETosis. In the same issue, Chen et al. also report a role for GSDMD in NETosis, and Rathkey et al. report necrosulfonamide to be an inhibitor of GSDMD.The death of a cell is an inevitable part of its biology. During homeostasis, most cells die through apoptosis. If homeostasis is disturbed, cell death can switch to proinflammatory forms of death, such as necroptosis, pyroptosis, or NETosis. We demonstrate that the formation of neutrophil extracellular traps (NETs), a special form of neutrophil cell death that releases chromatin structures to the extracellular space, is dependent on gasdermin D (GSDMD). GSDMD is a pore-forming protein and an executor of pyroptosis. We screened a chemical library and found a small molecule based on the pyrazolo-oxazepine scaffold that efficiently blocks NET formation and GSDMD-mediated pyroptotic cell death in human cells. During NETosis, GSDMD is proteolytically activated by neutrophil proteases and, in turn, affects protease activation and nuclear expansion in a feed-forward loop. In addition to the central role of GSDMD in pyroptosis, we propose that GSDMD also plays an essential function in NETosis.