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

Sci Immunol. 2018 Aug 24;3(26):eaar6689. doi: 10.1126/sciimmunol.aar6689.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / physiology*
  • Cell Death / physiology*
  • Extracellular Traps / physiology*
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice, Mutant Strains
  • Neoplasm Proteins / physiology*
  • Neutrophils / physiology*
  • Peptide Hydrolases / pharmacology
  • Phosphate-Binding Proteins


  • Apoptosis Regulatory Proteins
  • GSDMD protein, human
  • Gsdmd protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • Phosphate-Binding Proteins
  • Peptide Hydrolases