Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome.
Dying cells are capable of activating the innate immune system and inducing a sterile inflammatory response. Here, we show that necrotic cells are sensed by the Nlrp3 inflammasome resulting in the subsequent release of the proinflammatory cytokine IL-1beta. Necrotic cells produced by pressure disruption, hypoxic injury, or complement-mediated damage were capable of activating the Nlrp3 inflammasome. Nlrp3 inflammasome activation was triggered in part through ATP produced by mitochondria released from damaged cells. Neutrophilic influx into the peritoneum in response to necrotic cells in vivo was also markedly diminished in the absence of Nlrp3. Nlrp3-deficiency moreover protected animals against mortality, renal dysfunction, and neutrophil influx in an in vivo renal ischemic acute tubular necrosis model. These findings suggest that the inhibition of Nlrp3 inflammasome activity can diminish the acute inflammation and damage associated with tissue injury.
Iyer
Shankar S
SS
Division of Infectious Diseases, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
Pulskens
Wilco P
WP
Sadler
Jeffrey J
JJ
Butter
Loes M
LM
Teske
Gwendoline J
GJ
Ulland
Tyler K
TK
Eisenbarth
Stephanie C
SC
Florquin
Sandrine
S
Flavell
Richard A
RA
Leemans
Jaklien C
JC
Sutterwala
Fayyaz S
FS
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009336:Necrosis / Q000276:immunology*
D002352:Carrier Proteins; D016326:Extracellular Matrix Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D000255:Adenosine Triphosphate