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NAIP5/NLRC4 Inflammasomes Compounds Inhibit the NLRP1 Arsenic Trioxide and Other Arsenical Compounds Inhibit the NLRP1, NLRP3, and NAIP5/NLRC4 Inflammasomes This information is current as Nolan K. Maier, Devorah Crown, Jie Liu, Stephen H. Leppla of September 26, 2021. and Mahtab Moayeri J Immunol 2014; 192:763-770; Prepublished online 13 December 2013; doi: 10.4049/jimmunol.1301434 http://www.jimmunol.org/content/192/2/763 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2013/12/13/jimmunol.130143 Material 4.DC1 http://www.jimmunol.org/ References This article cites 55 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/192/2/763.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • 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 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Arsenic Trioxide and Other Arsenical Compounds Inhibit the NLRP1, NLRP3, and NAIP5/NLRC4 Inflammasomes Nolan K. Maier,* Devorah Crown,* Jie Liu,† Stephen H. Leppla,* and Mahtab Moayeri* Inflammasomes are large cytoplasmic multiprotein complexes that activate caspase-1 in response to diverse intracellular danger signals. Inflammasome components termed nucleotide-binding oligomerization domain–like receptor (NLR) proteins act as sensors for pathogen-associated molecular patterns, stress, or danger stimuli. We discovered that arsenicals, including arsenic trioxide and sodium arsenite, inhibited activation of the NLRP1, NLRP3, and NAIP5/NLRC4 inflammasomes by their respective activat- ing signals, anthrax lethal toxin, nigericin, and flagellin. These compounds prevented the autoproteolytic activation of caspase-1 and the processing and secretion of IL-1b from macrophages. Inhibition was independent of protein synthesis induction, proteasome-mediated protein breakdown, or kinase signaling pathways. Arsenic trioxide and sodium arsenite did not directly modify or inhibit the activity of preactivated recombinant caspase-1. Rather, they induced a cellular state inhibitory to both the Downloaded from autoproteolytic and substrate cleavage activities of caspase-1, which was reversed by the reactive oxygen species scavenger N-acetylcysteine but not by reducing agents or NO pathway inhibitors. Arsenicals provided protection against NLRP1-dependent anthrax lethal toxin–mediated cell death and prevented NLRP3-dependent neutrophil recruitment in a monosodium urate crystal inflammatory murine peritonitis model. These findings suggest a novel role in inhibition of the innate immune response for arsenical compounds that have been used as therapeutics for a few hundred years. The Journal of Immunology, 2014, 192: 763–770. http://www.jimmunol.org/ nflammasomes are large cytoplasmic multiprotein complexes domain–containing protein 4 (NLRC4) inflammasome by direct that form in response to intracellular danger signals. These binding (5, 6). The exact mechanisms by which many disparate I diverse danger signals include pathogen-derived stimuli such signals activate the “promiscuous” NLRP3 inflammasome are un- as bacterial toxins, flagellin, and dsDNA; self-derived molecules known (2). The end result of activation of all inflammasome sensors such as uric acid, amyloid crystals, cholesterol, and ATP; and sig- is the recruitment of caspase-1 to the sensor complex, followed by nals of environmental origin such as aluminum hydroxide, asbestos, its autoproteolytic activation. Activated caspase-1 then rapidly and UV radiation (for reviews, see Refs. 1, 2). The nucleotide- processes the proinflammatory cytokines IL-1b and IL-18 to mature binding oligomerization domain–like receptor leucine-rich repeat forms, allowing their secretion. These cytokines, which are the first by guest on September 26, 2021 proteins (NLRPs), which act as the sensor components of inflam- line of defense for the innate immune response, initiate a cascade of masomes, are activated by several mechanisms. For example, an- other immunological responses. Inflammasome activation is often thrax lethal toxin (LT), a bipartite toxin made of a receptor binding accompanied by a caspase-1–dependent rapid cell death known as moiety (protective Ag [PA]) and a protease (lethal factor [LF]), pyroptosis (for reviews, see Refs. 1, 2). activates rodent NLRP1 inflammasomes by cleaving them in an N- Not surprisingly, inflammasomes and the innate immune response terminal domain (3, 4). Flagellin activates the NLR family apoptosis play a key role in many infections (7). However, the proinflammatory inhibitory protein 5 (NAIP5)/NLR family caspase-1 recruitment response initiated by inflammasomes has also been implicated in metabolic disorders such as diabetes and inflammatory diseases such as gout and arthritis (8). Furthermore, polymorphisms in the *Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Dis- inflammasome NLR sensors are associated with diseases including eases, National Institutes of Health, Bethesda, MD 20892; and †Center for Molecular vitiligo, rheumatoid arthritis, and Alzheimer’s disease (1). The Medicine, National Heart Lung and Blood Institute, National Institutes of Health, chronic inflammation etiologically associated with numerous can- Bethesda, MD 20892 cers, most notably gastric, hepatic, and colorectal cancers, has also Received for publication May 31, 2013. Accepted for publication November 12, 2013. been linked to activation of these sensors (9). Thus, the role played This work was supported in part by the Intramural Research Program of the National by inflammasome-initiated inflammation in human disease has led Institute of Allergy and Infectious Diseases. to much interest in developing therapeutics targeting inflammasomes Address correspondence and reprint requests to Dr. Mahtab Moayeri, National In- or caspase-1. stitutes of Health Building 33, Room 1W20B, Bethesda, MD 20892. E-mail address: In this study, we show that activation of multiple inflammasomes [email protected] is inhibited by arsenical compounds. Sodium arsenite (NaAsO2) The online version of this article contains supplemental material. and arsenic trioxide (As2O3-Trisenox, a drug with established clinical Abbreviations used in this article: APL, acute promyelocytic leukemia; As2O3, arse- efficacy in treating a number of hematological cancers, including nic trioxide; BMDM, bone marrow–derived macrophage; Boc-D-CMK, Boc-Asp (OBzl)-chloromethylketone; FlaTox, toxin consisting of fusion protein between lethal acute promyelocytic leukemia (APL) and multiple myeloma (10), factor N terminus and flagellin and protective Ag; LF, lethal factor; LFn-Fla, fusion inhibit LT-induced inflammasome-dependent macrophage pyrop- protein between lethal factor N terminus and flagellin; LT, lethal toxin (toxin con- tosis when used at clinically relevant doses. These compounds not sisting of lethal factor and protective Ag); MSU, monosodium urate; NaAsO2, so- dium arsenite; NAC, N-acetylcysteine; NAIP5, NLR family apoptosis inhibitory only inhibit NLRP1 inflammasome activation by LT, but also the protein 5; NLR, nucleotide-binding oligomerization domain–like receptor; NLRC4, NAIP5/NLRC4 and NLRP3 inflammasome responses to their effec- NLR family caspase-1 recruitment domain–containing protein 4; NLRP, nucleotide- binding oligomerization domain–like receptor, leucine-rich repeat protein; PA, pro- tors. We found that arsenical compounds inhibit both caspase-1 tective Ag; PML, promyelocytic leukemia protein; ROS, reactive oxygen species. self-activating autoproteolytic activity as well as preactivated www.jimmunol.org/cgi/doi/10.4049/jimmunol.1301434 764 ARSENIC COMPOUNDS INHIBIT THE INFLAMMASOME recombinant caspase-1. The inhibition does not occur through or times (as described in the figure legends). Cells were then treated with direct modification or inhibition of caspase-1 enzymatic function, LT, FlaTox, or medium. Cell viability was assessed by MTT (Sigma-Aldrich) but rather through induction of a cytoplasmic environment in intact as previously described (14). In selected flow cytometry experiments, propidium iodide was used for viability analysis on a BD LSR II flow cells that is inhibitory to its activity. Our findings suggest a novel cytometer (BD Biosciences). role for arsenical compounds as inflammasome inhibitors, with possible off-target utility for treatment of inflammatory conditions, MEK, caspase-1, and IL-1b cleavage as well as a possible explanation of the mechanism for As2O3 ef- RAW264.7 and BALB/cJ BMDM cells were treated with LPS (1 mg/ml) for ficacy in cytokine-dependent hematological cancers. 2 h, with or without drugs (at doses and timing indicated in the figure legends), prior to addition of inflammasome activators (LT, FlaTox, or nigericin, at indicated doses). Cells were then lysed and processed for Materials and Methods Western blotting using primary Abs as previously described (14) in con- Reagents junction with infrared dye–conjugated secondary Abs
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