Necrotic Cells Trigger a Sterile Inflammatory Response Through the Nlrp3 Inflammasome

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2009 Nov 18

PMID 19918053

Citations 366

Authors

Shankar S Iyer

Wilco P Pulskens

Jeffrey J Sadler

Loes M Butter

Gwendoline J Teske

Tyler K Ulland

Stephanie C Eisenbarth

Sandrine Florquin

Richard A Flavell

Jaklien C Leemans

Fayyaz S Sutterwala

Affiliations

Soon will be listed here.

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.

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