Cutting edge: Necrosis activates the NLRP3 inflammasome.
Cells undergoing necrosis release endogenous danger signals that possess proinflammatory potential. In this study we show that mature IL-1beta and IL-18 are released by necrotic cells but not by apoptotic cells. We identify 7-bromoindirubin-3'-oxime, an indirubin oxime derivative that induces necrosis, as a potent inducer of caspase-1 activation and release of mature IL-1beta and IL-18. Inflammasome activation was triggered by other necrosis-inducing treatments but was not observed in response to apoptosis-inducing stimuli. Necrosis-induced inflammasome activation was mediated by the NLRP3 and ASC molecules. Release of IL-18 and IL-1beta in response to necrosis-inducing stimuli was observed in THP-1 macrophages and the MSTO-211H human mesothelioma cell line independently of LPS priming. Using the in vivo model of naphthalene-induced airway epithelial cell injury, we showed that necrosis activates the ASC inflammasome in vivo. Our study identifies a new mechanism through which necrosis generates proinflammatory molecules that contributes to the sterile inflammatory response.
Li
Hanfen
H
Department Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Ambade
Aditya
A
Re
Fabio
F
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000473:pathology; D006801:Humans; D007211:Indoles; D007249:Inflammation / Q000209:etiology* / Q000473:pathology; D020382:Interleukin-18; D053583:Interleukin-1beta; D008264:Macrophages / Q000473:pathology; D008654:Mesothelioma / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009336:Necrosis / Q000473:pathology*; D010091:Oximes; D012137:Respiratory System / Q000473:pathology*
C514974:7-bromoindirubin-3'-oxime; D002352:Carrier Proteins; D007211:Indoles; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D010091:Oximes