Uncontrolled activation of NLRP3 inflammasome initiates a series of human inflammatory diseases. Targeting NLRP3 inflammasome has attracted considerable attention in developing potential therapeutic interventions. Here, we reported that dehydrocostus lactone (DCL), a main component of Saussurea lappa from the traditional Chinese medicine, inhibited NLRP3 inflammasome-mediated caspase-1 activation and subsequent interleukin (IL)-1β production in primary mouse macrophages and human peripheral blood mononuclear cells and exerted an inhibitory effect on NLRP3-driven inflammation. Mechanistically, DCL significantly blocked the ASC oligomerization, which is essential for the assembly of activated inflammasome. Importantly, in vivo experiments showed that DCL reduced IL-1β secretion and peritoneal neutrophils recruitment in LPS-mediated inflammation mouse model, which is demonstrated to be NLRP3 dependent. These results suggest that DCL is a potent pharmacological inhibitor of NLRP3 inflammasome and may be developed as a therapeutic drug for treating NLRP3-associated diseases.

中文翻译：

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肋骨内酯脱水酶通过阻断ASC寡聚来抑制NLRP3炎性体的活化，并在体内预防LPS介导的炎症。

NLRP3炎性体的失控激活引发一系列人类炎症性疾病。靶向NLRP3炎性小体在开发潜在的治疗干预措施中引起了相当大的关注。在这里，我们报道了中草药雪莲的主要成分脱水肋内酯（DCL）抑制了NLRP3炎性体介导的caspase-1活化以及随后在原代小鼠巨噬细胞和人外周血单核中产生白介素（IL）-1β的作用。细胞并对NLRP3驱动的炎症产生抑制作用。从机理上讲，DCL显着阻断了ASC的低聚，这对于活化的炎性小体的组装至关重要。重要的，体内实验表明DCL减少了LPS介导的炎症小鼠模型中IL-1β的分泌和腹膜中性粒细胞的募集，这被证明是NLRP3依赖性的。这些结果表明DCL是NLRP3炎性体的有效药理抑制剂，可能被开发为治疗与NLRP3相关疾病的治疗药物。