Gasdermin D plays a vital role in the generation of neutrophil extracellular traps

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 - https://www.scopus.com/pages/publications/85056109673

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 -