Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps

TY - JOUR

T1 - Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps

AU - Chen, Kaiwen W

AU - Monteleone, Mercedes

AU - Boucher, Dave

AU - Sollberger, Gabriel

AU - Ramnath, Divya

AU - Condon, Nicholas D

AU - von Pein, Jessica B

AU - Broz, Petr

AU - Sweet, Matthew J

AU - Schroder, Kate

N1 - Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PY - 2018/8/24

Y1 - 2018/8/24

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis Regulatory Proteins/genetics

KW - Caspases/immunology

KW - Cell Death

KW - Citrobacter rodentium

KW - Cytosol/immunology

KW - Extracellular Traps/immunology

KW - Female

KW - Humans

KW - Inflammasomes/immunology

KW - Lipopolysaccharides

KW - Macrophages/immunology

KW - Male

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Neutrophils/immunology

KW - Salmonella Infections/immunology

KW - Salmonella enterica

U2 - 10.1126/sciimmunol.aar6676

DO - 10.1126/sciimmunol.aar6676

M3 - Article

C2 - 30143554

SN - 2470-9468

VL - 3

JO - Science Immunology

JF - Science Immunology

IS - 26

M1 - eaar6676

ER -