Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome.
Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome.
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DOI：
10.1016/j.redox.2017.04.020
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发表时间：
2017-08
期刊：
影响因子：
11.4
通讯作者：
Poynter ME
中科院分区：
文献类型：
--
作者：
Hoyt LR;Randall MJ;Ather JL;DePuccio DP;Landry CC;Qian X;Janssen-Heininger YM;van der Vliet A;Dixon AE;Amiel E;Poynter ME
酒精使用障碍在美国和全球都很常见，并与各种与炎症相关的共病疾病有关。其中许多疾病的发病机制是由NLRP3炎症体的激活推动的，NLRP3炎症体是一种多蛋白的细胞内模式识别受体复合体，促进促炎症细胞因子IL-1β和IL-18的切割和分泌。我们假设，长期暴露在乙醇中的白细胞会放大炎性小体的激活，这将有助于揭示与酒精中毒和异常的NLRP3炎性小体激活相关的疾病的机制。在这里，我们表明，长期酒精暴露的人外周血单个核细胞和小鼠巨噬细胞系(J774)在NLRP3激动剂刺激后，IL-1β的分泌增加，但不能用AIM2或NLRP1b激动剂刺激。NRLP3活性的增强是通过iNOS表达和NO产生的增加，以及长期接触乙醇的J774细胞线粒体膜去极化、氧耗率和ROS产生的增加，iNOS抑制剂SEITU、NO清除剂Carxy-PTIO和线粒体ROS清除剂MitoQ所抑制的。慢性乙醇暴露并未改变CE细胞的K+外流或锌离子稳态，尽管它确实导致细胞内NAD+浓度降低。长期给予乙醇脱氢酶介导的乙醇代谢产物乙醛可模拟慢性乙醇暴露，而乙醇脱氢酶抑制可阻止乙醇诱导的IL-1β高分泌。综上所述，这些结果表明，诱导型一氧化氮合酶和线粒体ROS的增加是慢性乙醇诱导的IL-1β高分泌的关键，长期接触乙醇代谢产物可能是NLRP3炎症体过度激活的介质。慢性乙醇暴露可增强NLRP3炎症组诱导的IL-1β分泌。NO和线粒体ROS介导慢性乙醇刺激的IL-1β分泌。酒精脱氢酶产生的代谢产物导致NLRP3炎症体过度激活。
Alcohol use disorders are common both in the United States and globally, and are associated with a variety of co-morbid, inflammation-linked diseases. The pathogenesis of many of these ailments are driven by the activation of the NLRP3 inflammasome, a multi-protein intracellular pattern recognition receptor complex that facilitates the cleavage and secretion of the pro-inflammatory cytokines IL-1β and IL-18. We hypothesized that protracted exposure of leukocytes to ethanol would amplify inflammasome activation, which would help to implicate mechanisms involved in diseases associated with both alcoholism and aberrant NLRP3 inflammasome activation. Here we show that long-term ethanol exposure of human peripheral blood mononuclear cells and a mouse macrophage cell line (J774) amplifies IL-1β secretion following stimulation with NLRP3 agonists, but not with AIM2 or NLRP1b agonists. The augmented NRLP3 activation was mediated by increases in iNOS expression and NO production, in conjunction with increases in mitochondrial membrane depolarization, oxygen consumption rate, and ROS generation in J774 cells chronically exposed to ethanol (CE cells), effects that could be inhibited by the iNOS inhibitor SEITU, the NO scavenger carboxy-PTIO, and the mitochondrial ROS scavenger MitoQ. Chronic ethanol exposure did not alter K+ efflux or Zn2+ homeostasis in CE cells, although it did result in a lower intracellular concentration of NAD+. Prolonged administration of acetaldehyde, the product of alcohol dehydrogenase (ADH) mediated metabolism of ethanol, mimicked chronic ethanol exposure, whereas ADH inhibition prevented ethanol-induced IL-1β hypersecretion. Together, these results indicate that increases in iNOS and mitochondrial ROS production are critical for chronic ethanol-induced IL-1β hypersecretion, and that protracted exposure to the products of ethanol metabolism are probable mediators of NLRP3 inflammasome hyperactivation. Chronic ethanol exposure amplifies NLRP3 inflammasome-induced IL-1β secretion. NO and mitochondrial ROS mediate chronic ethanol-augmented IL-1β secretion. Alcohol dehydrogenase-generated metabolites cause NLRP3 inflammasome over-activation.