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Inflammasome Cutting Edge: Necrosis Activates the NLRP3 Cutting Edge: Necrosis Activates the NLRP3 Inflammasome Hanfen Li, Aditya Ambade and Fabio Re This information is current as J Immunol 2009; 183:1528-1532; Prepublished online 13 of September 28, 2021. July 2009; doi: 10.4049/jimmunol.0901080 http://www.jimmunol.org/content/183/3/1528 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2009/07/14/jimmunol.090108 Material 0.DC1 References This article cites 24 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/183/3/1528.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Cutting Edge Cutting Edge: Necrosis Activates the NLRP3 Inflammasome1 Hanfen Li, Aditya Ambade, and Fabio Re2 Cells undergoing necrosis release endogenous danger IL-1 family (IL-1␤, IL-18, and IL-33). The protease caspase-1 signals that possess proinflammatory potential. In this and the adaptor molecule ASC are also part of the inflamma- study we show that mature IL-1␤ and IL-18 are released some. The function of NLR is to detect the presence of micro- by necrotic cells but not by apoptotic cells. We identify bial products, toxins, and danger signals in the cytoplasm lead- 7-bromoindirubin-3؅-oxime, an indirubin oxime deriv- ing to caspase-1 activation, a necessary step for the processing ␤ ative that induces necrosis, as a potent inducer of and secretion of the immature forms of IL-1 , IL-18, and IL- caspase-1 activation and release of mature IL-1␤ and IL- 33. One of the best-characterized NLRs is NLRP3 (also known as cryopyrin and Nalp3). This molecule mediates inflamma- 18. Inflammasome activation was triggered by other ne- Downloaded from some activation in response to several intracellular bacteria (3) crosis-inducing treatments but was not observed in re- and viruses (4, 5), danger signals such as extracellular ATP and sponse to apoptosis-inducing stimuli. Necrosis-induced uric acid crystals (monosodium urate) (6), and particles of dif- inflammasome activation was mediated by the NLRP3 ␤ ferent origin such as asbestos fibers (7), silica particles (8, 9), and ASC molecules. Release of IL-18 and IL-1 in re- and alum crystals, as we and other groups have recently dem- sponse to necrosis-inducing stimuli was observed in onstrated (10–13). The differences in the structure and func- THP-1 macrophages and the MSTO-211H human me- tion of the factors reported to activate the NLRP3-inflamma- http://www.jimmunol.org/ sothelioma cell line independently of LPS priming. Us- some make it unlikely that they directly interact with the ing the in vivo model of naphthalene-induced airway ep- receptor. Rather, the emerging consensus is that NLRP3 may ithelial cell injury, we showed that necrosis activates the recognize a “messenger molecule” that is generated inside the ASC inflammasome in vivo. Our study identifies a new cell in response to the insult that these agonists may cause. Re- mechanism through which necrosis generates proin- cently published evidence suggests that lysosome destabiliza- flammatory molecules that contributes to the sterile in- tion and the protease cathepsin B are critically involved in flammatory response. The Journal of Immunology, NLRP3 activation (8). 2009, 183: 1528–1532. Considering the evolutionary advantage that detection of tis- by guest on September 28, 2021 sue damage confers to the organism, it is conceivable that, in addition to passive release of danger signals, necrotic cells may ecrotic cells release endogenous molecules, such as actively generate proinflammatory molecules as result of the ac- heath shock proteins, uric acid, ATP, and DNA tivation of endogenous signaling pathways. In this study we re- N that alert the innate immune system of the danger port that the NLRP3 inflammasome is activated in necrotic but associated with tissue damage and infection (1). These mol- not in apoptotic cells, leading to the release of IL-1␤ and IL-18. ecules act as endogenous “danger signals” by activating a va- Our study identifies a new mechanism through which necrosis riety of pattern recognition receptors, including TLR and generates proinflammatory molecules that contribute to the Nod-like receptors (NLR).3 As a result, necrotic cells and sterile inflammatory response. several danger signals directly trigger proinflammatory re- sponses, potentiate signaling by classical proinflammatory Materials and Methods stimuli, and possess adjuvant capacity. Inflammation trig- Mice gered by tissue damage in the absence of infection is referred NLRP3Ϫ/Ϫ, ASCϪ/Ϫ, and NLRC4Ϫ/Ϫ mice on C57BL/6 background were to as sterile inflammatory response. kindly provided by Dr. V. Dixit, Genentech, South San Francisco, CA. Age Members of the NLR family are key components of the in- and sex-matched C57BL/6 were purchased from The Jackson Laboratory. All experiments using mice were approved by the University of Tennessee flammasome (2), a multiprotein cytoplasmic complex that reg- Health Science Center Institutional Animal Care and Use Committee ulates secretion and bioactivity of cytokines belonging to the (Memphis, TN). Department Molecular Sciences, University of Tennessee Health Science Center, Mem- 3 Abbreviations used in this paper: NLR, Nod-like receptor; AEBSF, 4-(2-aminoethyl)- phis, TN 38163 benzenesulfonyl fluoride; BAL, bronchoalveolar lavage; 7BIO, 7-bromoindirubin-3Ј- oxime; BMM, bone marrow-derived mononuclear cell; HMGB1, high mobility group box Received for publication April 3, 2009. Accepted for publication June 10, 2009. 1; IO, indirubin oxime; LDH, lactate dehydrogenase; STS, staurosporine; Z-YVAD- The costs of publication of this article were defrayed in part by the payment of page charges. FMK, N-benzyloxycarbonyl-Tyr-Val-Ala-Asp-fluoromethyl ketone. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 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: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.0901080 The Journal of Immunology 1529 Reagents Indirubin derivatives (resuspended in DMSO at 25 mM) and the caspase-1 inhibitor N-benzyloxycarbonyl-Tyr-Val-Ala-Asp-fluoromethyl ketone (Z- YVAD-FMK) were purchased from Axxora. Alum (Alhydrogel) was from Sigma-Aldrich. The cathepsin B inhibitor CA-074-Me was from Biomol International. All other chemicals were from Sigma-Aldrich. The following Abs were used: rabbit anti-caspase-1 (Upstate Biotechnologies), goat anti- mIL-1␤ (R&D Systems), anti-human IL-1␤ 3ZD mAb (Preclinical Repos- itory, Biological Research Branch, National Cancer Institute), and rabbit anti-HMGB1 (where HMGB1 is high mobility group box 1; Santa Cruz Biotechnology). Human cell lines The THP-1 macrophages and MSTO-211H lung mesothelioma human cell lines were obtained from American Type Culture Collection and grown in RPMI 1640 with 10% FCS. PBMC and bone marrow-derived mononuclear cell (BMM) isolation Human PBMC were isolated from leukopacks by Ficoll-Histopaque density gradient centrifugation. Mouse BMM were generated by incubating bone mar- row in RPMI 1640 with FCS and supplemented with recombinant murine FIGURE 1. 7BIO activates the inflammasome. THP-1 (A) or PBMC Downloaded from GM-CSF (20 ng/ml) for 8 days. This procedure routinely results in 60–80% (B–D) were primed for 4 h with LPS (3 ng/ml) and stimulated for additional CD11cϩ dendritic cells. 6 h with the indicated indirubin derivatives (25 ␮MinA and 5, 25, and 125 ␮ ␤ ␤ Cytokine measurements MinB) and inhibitors. A, Human IL-1 (hIL-1 ) was measured in con- ditioned supernatants of cells stimulated with 5-iodine-indirubin-3Ј-oxime Cytokine levels in conditioned supernatants and bronchoalveolar lavage (BAL) (5IIO), 6-bromoindirubin-3Ј-oxime (6BIO), 7BIO, IO, indirubin (Indi), fluids were measured by ELISA using the following paired Abs kits: human 7BIO-Me, and alum crystals. B, Primed PBMC were also stimulated with IL-1␤ and human IL-18 (R&D Systems), murine IL-1␤ (eBioscience), and http://www.jimmunol.org/ 7BIO for 1, 3, and7horwith 7BIO, 6BIO, and indirubin at 125, 25, and murine IL-18 (MBL Nagoya, Japan). 5 ␮M. C, The presence of the immature (Pro-) and mature forms of Statistical analysis caspase-1 and IL-1␤ in cell culture supernatants was analyzed by immuno- blotting. C, CA-074-Me; Z, Z-YVAD-FMK. D, Inflammasome activation Ϯ All data were expressed as mean SEM. Student’s t test was used for statistical by 7BIO was blocked by treatment with Z-YVAD-FMK (ZYVAD) at 10 evaluation of the results. Significance was set at p Ͻ 0.05. ␮M) and CA-074-Me (CA094) but not by cytochalasin D (CytoD) or by uricase at 10 U/ml, apyrase at 2 U/ml, and oxidized ATP (oATP) at 0.25 ␮M. Results and Discussion Indirubin oxime (IO) derivative 7BIO activates the inflammasome In a search for small molecules capable of activating the inflam- activation by 7BIO is not mediated by the release of endoge- by guest on September 28, 2021 masome, we identified 7-bromoindirubin-3Ј-oxime (7BIO), an nous danger signals like monosodium urate or ATP.
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