Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps

Kaiwen W Chen, Mercedes Monteleone, Dave Boucher, Gabriel Sollberger, Divya Ramnath, Nicholas D Condon, Jessica B von Pein, Petr Broz, Matthew J Sweet, Kate Schroder

Research output: Contribution to journalArticlepeer-review


Neutrophil extrusion of neutrophil extracellular traps (NETs) and concomitant cell death (NETosis) provides host defense against extracellular pathogens, whereas macrophage death by pyroptosis enables defense against intracellular pathogens. We report the unexpected discovery that gasdermin D (GSDMD) connects these cell death modalities. We show that neutrophil exposure to cytosolic lipopolysaccharide or cytosolic Gram-negative bacteria (Salmonella ΔsifA and Citrobacter rodentium) activates noncanonical (caspase-4/11) inflammasome signaling and triggers GSDMD-dependent neutrophil death. GSDMD-dependent death induces neutrophils to extrude antimicrobial NETs. Caspase-11 and GSDMD are required for neutrophil plasma membrane rupture during the final stage of NET extrusion. Unexpectedly, caspase-11 and GSDMD are also required for early features of NETosis, including nuclear delobulation and DNA expansion; this is mediated by the coordinate actions of caspase-11 and GSDMD in mediating nuclear membrane permeabilization and histone degradation. In vivo application of deoxyribonuclease I to dissolve NETs during murine Salmonella ΔsifA challenge increases bacterial burden in wild-type but not in Casp11-/- and Gsdmd -/- mice. Our studies reveal that neutrophils use an inflammasome- and GSDMD-dependent mechanism to activate NETosis as a defense response against cytosolic bacteria.

Original languageEnglish
Article numbereaar6676
Number of pages11
JournalScience Immunology
Issue number26
Publication statusPublished - 24 Aug 2018

Bibliographical note

Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.


  • Animals
  • Apoptosis Regulatory Proteins/genetics
  • Caspases/immunology
  • Cell Death
  • Citrobacter rodentium
  • Cytosol/immunology
  • Extracellular Traps/immunology
  • Female
  • Humans
  • Inflammasomes/immunology
  • Lipopolysaccharides
  • Macrophages/immunology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils/immunology
  • Salmonella Infections/immunology
  • Salmonella enterica

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