title: Arsenic trioxide and other arsenical compounds inhibit the NLRP1, NLRP3, and NAIP5/NLRC4 inflammasomes.
abstract: 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 activating signals, anthrax lethal toxin, nigericin, and flagellin. These compounds prevented the autoproteolytic activation of caspase-1 and the processing and secretion of IL-1β 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 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.
authors: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors: Nolan K
authors: NK
authors: Maier
authors: Devorah
authors: D
authors: Crown
authors: Jie
authors: J
authors: Liu
authors: Stephen H
authors: SH
authors: Leppla
authors: Mahtab
authors: M
authors: Moayeri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D018053:Arsenites / Q000494:pharmacology; D001427:Bacterial Toxins / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D005408:Flagellin / Q000494:pharmacology; D007113:Immunity, Innate / Q000187:drug effects; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009550:Nigericin / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D000071156:Promyelocytic Leukemia Protein; D059748:Proteolysis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017670:Sodium Compounds / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins; D001152:Arsenicals; D018053:Arsenites; D001427:Bacterial Toxins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; C529636:NALP1 protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C496806:Naip5 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein; D009589:Nitrogen Oxides; C492716:Nlrp3 protein, mouse; D009687:Nuclear Proteins; D010087:Oxides; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D017382:Reactive Oxygen Species; D017670:Sodium Compounds; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C030325:anthrax toxin; D005408:Flagellin; C017947:sodium arsenite; D020170:Caspase 1; D009550:Nigericin; D000077237:Arsenic Trioxide