Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 2014 Jan 15;192(2):763-70. doi: 10.4049/jimmunol.1301434. Epub 2013 Dec 13.
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.
炎症小体是一种大型细胞质多蛋白复合物，可响应各种细胞内危险信号激活半胱氨酸蛋白酶-1。炎症小体的组成部分，称为核苷酸结合寡聚化结构域样受体 (NLR) 蛋白，作为病原体相关分子模式、应激或危险刺激的传感器。我们发现，砷剂，包括三氧化二砷和亚砷酸钠，通过其各自的激活信号（炭疽致死毒素、 Nigericin 和鞭毛蛋白）抑制 NLRP1、NLRP3 和 NAIP5/NLRC4 炎症小体的激活。这些化合物阻止了半胱氨酸蛋白酶-1 的自水解激活以及巨噬细胞中白细胞介素-1β 的加工和分泌。抑制作用不依赖于蛋白质合成诱导、蛋白酶体介导的蛋白质降解或激酶信号通路。三氧化二砷和亚砷酸钠不会直接修饰或抑制预先激活的重组半胱氨酸蛋白酶-1 的活性。相反，它们诱导一种细胞状态，抑制半胱氨酸蛋白酶-1 的自水解和底物切割活性，这种抑制状态可被活性氧清除剂 N-乙酰半胱氨酸逆转，但不能被还原剂或 NO 途径抑制剂逆转。砷剂可提供针对 NLRP1 依赖性炭疽致死毒素介导的细胞死亡的保护，并在单钠尿酸盐晶体炎症性小鼠腹膜炎模型中防止 NLRP3 依赖性中性粒细胞募集。这些发现表明，砷化合物在抑制先天免疫反应方面具有新的作用，这些化合物已经作为治疗药物使用了数百年。
