Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
Wuzhongpei Memorial Hospital of Shunde, Foshan, China.
Front Immunol. 2021 Feb 17;12:632606. doi: 10.3389/fimmu.2021.632606. eCollection 2021.
Taraxasterol (TAS) is an active ingredient of Dandelion ( Hand. -Mazz.), a medicinal plant that has long been used in China for treatment of inflammatory disorders. But the underlying mechanism for its therapeutic effects on inflammatory disorders is not completely clear. Inflammasome activation is a critical step of innate immune response to infection and aseptic inflammation. Among the various types of inflammasome sensors that has been reported, NLR family pyrin domain containing 3 (NLRP3) is implicated in various inflammatory diseases and therefore has been most extensively studied. In this study, we aimed to explore whether TAS could influence NLPR3 inflammasome activation in macrophages. The results showed that TAS dose-dependently suppressed the activation of caspase-1 in lipopolysaccharide (LPS)-primed murine primary macrophages upon nigericin treatment, resulting in reduced mature interleukin-1β (IL-1β) release and gasdermin D (GSDMD) cleavage. TAS greatly reduced ASC speck formation upon the stimulation of nigericin or extracellular ATP. Consistent with reduced cleavage of GSDMD, nigericin-induced pyroptosis was alleviated by TAS. Interestingly, TAS time-dependently suppressed the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and mTORC2 signaling induced by LPS priming. Like TAS, both INK-128 (inhibiting both mTORC1 and mTORC2) and rapamycin (inhibiting mTORC1 only) also inhibited NLRP3 inflammasome activation, though their effects on mTOR signaling were different. Moreover, TAS treatment alleviated mitochondrial damage by nigericin and improved mouse survival from bacterial infection, accompanied by reduced IL-1β levels . Collectively, by inhibiting the NLRP3 inflammasome activation, TAS displayed anti-inflammatory effects likely through regulation of the mTOR signaling in macrophages, highlighting a potential action mechanism for the anti-inflammatory activity of Dandelion in treating inflammation-related disorders, which warrants further clinical investigation.
蒲公英萜醇（TAS）是蒲公英（Hand.-Mazz.）的一种活性成分，蒲公英是一种中国传统草药，长期以来一直被用于治疗炎症性疾病。但其对炎症性疾病的治疗作用的潜在机制尚不完全清楚。炎性体激活是固有免疫对感染和无菌性炎症反应的关键步骤。在已报道的各种炎性体传感器中，富含 N 端pyrin 结构域的白细胞介素-1 受体相关激酶 3（NLRP3）与各种炎症性疾病有关，因此研究最为广泛。在这项研究中，我们旨在探讨 TAS 是否会影响巨噬细胞中 NLRP3 炎性体的激活。结果表明，TAS 呈剂量依赖性抑制脂多糖（LPS）预刺激的小鼠原代巨噬细胞在 Nigericin 处理时 caspase-1 的激活，导致成熟白细胞介素-1β（IL-1β）释放和 Gasdermin D（GSDMD）裂解减少。TAS 极大地减少了 Nigericin 或细胞外 ATP 刺激时 ASC 斑点的形成。与 GSDMD 裂解减少一致，TAS 缓解了 Nigericin 诱导的细胞焦亡。有趣的是，TAS 呈时间依赖性抑制 LPS 预刺激诱导的机械靶蛋白（mTOR）复合物 1（mTORC1）和 mTORC2 信号。与 TAS 相似，INK-128（抑制 mTORC1 和 mTORC2）和雷帕霉素（仅抑制 mTORC1）均抑制 NLRP3 炎性体的激活，尽管它们对 mTOR 信号的影响不同。此外，TAS 处理可减轻 Nigericin 引起的线粒体损伤并提高小鼠对细菌感染的存活率，同时降低 IL-1β 水平。综上所述，TAS 通过抑制 NLRP3 炎性体的激活，显示出抗炎作用，可能是通过调节巨噬细胞中的 mTOR 信号，这突显了蒲公英在治疗炎症相关疾病中的抗炎活性的潜在作用机制，值得进一步的临床研究。
Zotero 插件
