The nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing (NLRP) 3 inflammasome is a multiprotein complex that triggers Caspase-1-mediated IL-1β production and pyroptosis, and its dysregulation is associated with the pathogenesis of inflammatory diseases. 1′-Acetoxychavicol acetate (ACA) is a natural compound in the rhizome of tropical ginger Alpinia species with anti-microbial, anti-allergic and anti-cancer properties. In this study, we found that ACA suppressed NLRP3 inflammasome activation in mouse bone marrow-derived macrophages and human THP-1 monocytes. ACA inhibited Caspase-1 activation and IL-1β production by NLRP3 agonists such as nigericin, monosodium urate (MSU) crystals, and ATP. Moreover, it suppressed oligomerization of the adapter molecule, apoptosis-associated speck-like protein containing a CARD (ASC), and Caspase-1-mediated cleavage of pyroptosis executor Gasdermin D. Mechanistically, ACA inhibited generation of mitochondrial reactive oxygen species (ROS) and prevented release of oxidized mitochondrial DNA, which trigger NLRP3 inflammasome activation. ACA also prevented NLRP3 inflammasome activation in vivo, as evidenced in the MSU crystal-induced peritonitis and dextran sodium sulfate-induced colitis mouse models accompanied by decreased Caspase-1 activation. Thus, ACA is a potent inhibitor of the NLRP3 inflammasome for prevention of NLRP3-associated inflammatory diseases.

中文翻译：

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1'-Acetoxychavicol acetate 通过线粒体 ROS 抑制抑制 NLRP3 依赖性炎症小体活化

核苷酸结合寡聚结构域样受体 (NLR) 家族含有吡啶结构域 (NLRP) 3 炎性体是一种多蛋白复合物，可触发 Caspase-1 介导的 IL-1β 产生和细胞焦亡，其失调与炎性疾病的发病机制有关. 1'-Acetoxychavicol acetate (ACA) 是热带生姜高良姜根茎中的一种天然化合物具有抗微生物、抗过敏和抗癌特性的物种。在这项研究中，我们发现 ACA 抑制了小鼠骨髓来源的巨噬细胞和人 THP-1 单核细胞中 NLRP3 炎症小体的活化。ACA 抑制 NLRP3 激动剂如尼日利亚菌素、尿酸单钠 (MSU) 晶体和 ATP 的 Caspase-1 活化和 IL-1β 产生。此外，它还抑制接头分子的寡聚化、含有 CARD (ASC) 的凋亡相关斑点样蛋白和 Caspase-1 介导的焦亡执行者 Gasdermin D 的切割。从机制上讲，ACA 抑制线粒体活性氧 (ROS) 的产生并阻止氧化线粒体 DNA 的释放，从而触发 NLRP3 炎性体激活。ACA 还阻止了体内NLRP3 炎症小体的激活，正如 MSU 晶体诱导的腹膜炎和葡聚糖硫酸钠诱导的结肠炎小鼠模型所证明的那样，伴随着 Caspase-1 活化减少。因此，ACA 是 NLRP3 炎性体的有效抑制剂，可用于预防 NLRP3 相关的炎性疾病。