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YOUAH Home » science news » Arsenic Trioxide and Other Arsenical Compounds Inhibit the NLRP1 NLRP3 and NAIP5/NLRC4 Inflammasomes INNATE IMMUNITY AND INFLAMMATION]
Friday, 20 Oct 2017

Arsenic Trioxide and Other Arsenical Compounds Inhibit the NLRP1 NLRP3 and NAIP5/NLRC4 Inflammasomes INNATE IMMUNITY AND INFLAMMATION]

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.

Read more: Arsenic Trioxide and Other Arsenical Compounds Inhibit the NLRP1 NLRP3 and NAIP5/NLRC4 Inflammasomes INNATE IMMUNITY AND INFLAMMATION]

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