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: Nolan K Maier, Devorah Crown, Jie Liu, Stephen H Leppla, Mahtab Moayeri
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 2 Pg. 763-70 (Jan 15 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24337744 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antigens, Bacterial
• Apoptosis Regulatory Proteins
• Arsenicals
• Arsenites
• Bacterial Toxins
• Calcium-Binding Proteins
• Carrier Proteins
• Inflammasomes
• Interleukin-1beta
• Ipaf protein, mouse
• NALP1 protein, mouse
• NLR Family, Pyrin Domain-Containing 3 Protein
• Naip5 protein, mouse
• Neuronal Apoptosis-Inhibitory Protein
• Nitrogen Oxides
• Nlrp3 protein, mouse
• Nuclear Proteins
• Oxides
• Pml protein, mouse
• Promyelocytic Leukemia Protein
• Reactive Oxygen Species
• Sodium Compounds
• Transcription Factors
• Tumor Suppressor Proteins
• anthrax toxin
• Flagellin
• sodium arsenite
• Caspase 1
• Nigericin
• Arsenic Trioxide

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Antigens, Bacterial (pharmacology)
• Apoptosis Regulatory Proteins (metabolism)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Arsenites (pharmacology)
• Bacterial Toxins (pharmacology)
• Calcium-Binding Proteins (metabolism)
• Carrier Proteins (metabolism)
• Caspase 1 (metabolism)
• Cell Death (drug effects)
• Cell Line
• Flagellin (pharmacology)
• Immunity, Innate (drug effects)
• Inflammasomes (drug effects, metabolism)
• Interleukin-1beta (metabolism)
• Macrophages (drug effects, metabolism)
• Mice
• Mice, Inbred BALB C
• NLR Family, Pyrin Domain-Containing 3 Protein
• Neuronal Apoptosis-Inhibitory Protein (metabolism)
• Neutrophils (drug effects, metabolism)
• Nigericin (pharmacology)
• Nitrogen Oxides (metabolism)
• Nuclear Proteins (metabolism)
• Oxides (pharmacology)
• Promyelocytic Leukemia Protein
• Proteolysis (drug effects)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Sodium Compounds (pharmacology)
• Transcription Factors (metabolism)
• Tumor Suppressor Proteins (metabolism)