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Sci Immunol. 2018 Aug 24;3(26). pii: eaar6676. doi: 10.1126/sciimmunol.aar6676.

Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps.

Author information

1
Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, University of Queensland, St Lucia Brisbane 4072, Queensland, Australia.
2
Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
3
Max Planck Institute for Infection Biology, Department of Cellular Microbiology, Charitéplatz 1, Berlin.

Abstract

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.

PMID:
30143554
DOI:
10.1126/sciimmunol.aar6676

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