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Cutting Edge: Necrosis Activates the NLRP3 Inflammasome¹

Department Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163

Cells undergoing necrosis release endogenous danger signals that possess proinflammatory potential. In this study we show that mature IL-1β 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-1β 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-1β 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R21AI076835 (to F.R.).

² Address correspondence and reprint requests to Dr. Fabio Re, Department Molecular Sciences, University of Tennessee Health Science Center, 858 Madison Avenue, Memphis, TN 38163. E-mail address: fre{at}utmem.edu

³ Abbreviations used in this paper: NLR, Nod-like receptor; AEBSF, 4-(2-aminoethyl)-benzenesulfonyl fluoride; BAL, bronchoalveolar lavage; 7BIO, 7-bromoindirubin-3'-oxime; BMM, bone marrow-derived mononuclear cell; HMGB1, high mobility group box 1; IO, indirubin oxime; LDH, lactate dehydrogenase; STS, staurosporine; Z-YVAD-FMK, N-benzyloxycarbonyl-Tyr-Val-Ala-Asp-fluoromethyl ketone.

⁴ The online version of this article contains supplemental material.

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