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Arsenic trioxide and other arsenical compounds inhibit the NLRP1, NLRP3, and NAIP5/NLRC4 inflammasomes

Friday, November 08, 2013 — Poster Session IV

2:00 p.m. – 4:00 p.m.

FAES Academic Center (Upper-Level Terrace)




  • NK Maier
  • D Crown
  • J Liu
  • SH Leppla
  • M Moayeri


Inflammasomes are large cytoplasmic multi-protein complexes that activate caspase-1 in response to diverse intracellular danger signals. Inflammasome components termed NOD-like receptor proteins (NLRs) act as sensors for pathogen associated molecular patterns, stress or danger stimuli. Arsenicals, including arsenic trioxide and sodium arsenite, prevent 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 or proteasome-mediated protein breakdown. Arsenic trioxide and sodium arsenite did not directly modify or inhibit the activity of pre-activated recombinant caspase-1. Rather, these compounds induced a cellular state inhibitory to both the autoproteolytic and substrate cleavage activities of caspase-1. Arsenical compound inhibition of inflammasome activation and IL-1β release was reversed by the reactive oxygen species (ROS) scavenger N-acetyl-cysteine. Arsenicals protected against NLRP1-dependent anthrax lethal toxin-mediated death and prevented NLRP3-dependent neutrophil recruitment in a monosodium-urate crystal inflammatory murine gout model. These findings suggest a novel role in inhibition of the innate immune response for arsenical compounds which have been used as therapeutics for a few hundred years.

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