TY - JOUR
T1 - Gasdermin D plays a vital role in the generation of neutrophil extracellular traps
AU - Sollberger, Gabriel
AU - Choidas, Axel
AU - Burn, Garth Lawrence
AU - Habenberger, Peter
AU - Lucrezia, Raffaella Di
AU - Kordes, Susanne
AU - Menninger, Sascha
AU - Eickhoff, Jan
AU - Nussbaumer, Peter
AU - Klebl, Bert
AU - Krüger, Renate
AU - Herzig, Alf
AU - Zychlinsky, Arturo
PY - 2018/8
Y1 - 2018/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85056109673&partnerID=8YFLogxK
U2 - 10.1126/sciimmunol.aar6689
DO - 10.1126/sciimmunol.aar6689
M3 - Article
C2 - 30143555
AN - SCOPUS:85056109673
SN - 2470-9468
VL - 3
SP - 1
EP - 12
JO - Science Immunology
JF - Science Immunology
IS - 26
M1 - eaar6689
ER -