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 disrup...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 48; p. 20388
Main Authors: Iyer, Shankar S, Pulskens, Wilco P, Sadler, Jeffrey J, Butter, Loes M, Teske, Gwendoline J, Ulland, Tyler K, Eisenbarth, Stephanie C, Florquin, Sandrine, Flavell, Richard A, Leemans, Jaklien C, Sutterwala, Fayyaz S
Format: Journal Article
Language:English
Published: United States 01.12.2009
Subjects:
Adenosine Triphosphate - metabolism
Animals
Carrier Proteins - immunology
Carrier Proteins - metabolism
Enzyme-Linked Immunosorbent Assay
Extracellular Matrix Proteins - metabolism
Inflammation - immunology
Interleukin-1beta - immunology
Mice
Mice, Inbred C57BL
Mitochondria - metabolism
Necrosis - immunology
NLR Family, Pyrin Domain-Containing 3 Protein
ISSN:1091-6490, 1091-6490
Online Access:Get more information
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Summary: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.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.0908698106