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Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20388-93. doi: 10.1073/pnas.0908698106. Epub 2009 Nov 16.

Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome.

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1
Division of Infectious Diseases, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.

Abstract

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.

PMID:
19918053
PMCID:
PMC2787135
DOI:
10.1073/pnas.0908698106
[Indexed for MEDLINE]
Free PMC Article
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