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

Gabriel Sollberger, Axel Choidas, Garth Lawrence Burn, Peter Habenberger, Raffaella Di Lucrezia, Susanne Kordes, Sascha Menninger, Jan Eickhoff, Peter Nussbaumer, Bert Klebl, Renate Krüger, Alf Herzig, Arturo Zychlinsky (Lead / Corresponding author)

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83 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbereaar6689
Pages (from-to)1-12
Number of pages12
JournalScience Immunology
Volume3
Issue number26
Early online date24 Aug 2018
DOIs
Publication statusPublished - Aug 2018

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    Sollberger, G., Choidas, A., Burn, G. L., Habenberger, P., Lucrezia, R. D., Kordes, S., Menninger, S., Eickhoff, J., Nussbaumer, P., Klebl, B., Krüger, R., Herzig, A., & Zychlinsky, A. (2018). Gasdermin D plays a vital role in the generation of neutrophil extracellular traps. Science Immunology, 3(26), 1-12. [eaar6689]. https://doi.org/10.1126/sciimmunol.aar6689