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
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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.
AbstractList	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.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. 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.
Author	Teske, Gwendoline J Leemans, Jaklien C Iyer, Shankar S Eisenbarth, Stephanie C Pulskens, Wilco P Flavell, Richard A Butter, Loes M Sutterwala, Fayyaz S Sadler, Jeffrey J Florquin, Sandrine Ulland, Tyler K
Author_xml	– sequence: 1 givenname: Shankar S surname: Iyer fullname: Iyer, Shankar S organization: Division of Infectious Diseases, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA – sequence: 2 givenname: Wilco P surname: Pulskens fullname: Pulskens, Wilco P – sequence: 3 givenname: Jeffrey J surname: Sadler fullname: Sadler, Jeffrey J – sequence: 4 givenname: Loes M surname: Butter fullname: Butter, Loes M – sequence: 5 givenname: Gwendoline J surname: Teske fullname: Teske, Gwendoline J – sequence: 6 givenname: Tyler K surname: Ulland fullname: Ulland, Tyler K – sequence: 7 givenname: Stephanie C surname: Eisenbarth fullname: Eisenbarth, Stephanie C – sequence: 8 givenname: Sandrine surname: Florquin fullname: Florquin, Sandrine – sequence: 9 givenname: Richard A surname: Flavell fullname: Flavell, Richard A – sequence: 10 givenname: Jaklien C surname: Leemans fullname: Leemans, Jaklien C – sequence: 11 givenname: Fayyaz S surname: Sutterwala fullname: Sutterwala, Fayyaz S
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/19918053$$D View this record in MEDLINE/PubMed
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Snippet	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...
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SubjectTerms	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
Title	Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome
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