Scoparone suppresses mitophagy-mediated NLRP3 inflammasome activation in inflammatory diseases
Scoparone suppresses mitophagy-mediated NLRP3 inflammasome activation in inflammatory diseases
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Scoparone 抑制炎症疾病中线粒体自噬介导的 NLRP3 炎症小体激活
DOI：
10.1038/s41401-022-01028-9
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发表时间：
2022-12-15
影响因子：
8.2
通讯作者：
Xu，An-long
中科院分区：
文献类型：
--
作者：
Feng，Wan-di;Wang，Yao;Xu，An-long
最近的证据表明，靶向NLRP3炎性小体激活是治疗炎性小体驱动疾病的重要手段。天冬Scoparone是一种从中草药bartemisia capillarisThunb中分离出来的天然化合物，具有抗炎活性。本研究探讨了天scopone对炎性疾病中NLRP3炎性小体激活的影响。在lps启动、ATP或奈及利菌素刺激的小鼠巨噬细胞J774A.1细胞和骨髓源性巨噬细胞（bmdm）中，前处理scoparone （50 μM）可显著抑制典型和非典型NLRP3炎性体的激活，其证据是抑制caspase-1裂解、gsdmd介导的焦亡、成熟IL-1β分泌和ASC斑点的形成。然后，我们对scoparone预处理的bmdm进行转录组分析，发现差异表达基因在线粒体活性氧（ROS）代谢过程、线粒体翻译和组装过程以及炎症反应中显著富集。我们在J774A.1细胞和bmdm中证明，天scoparone促进线粒体自噬，这是一种控制线粒体质量、减少ROS产生和随后NLRP3炎性体激活的已知机制。3-甲基腺嘌呤阻断线粒体自噬（3-MA, 5 mM）逆转了scoparone对小鼠巨噬细胞线粒体损伤和炎症的保护作用。此外，scoparone （50 mg/kg）通过抑制小鼠细菌性肠炎和感染性休克模型的NLRP3激活，具有显著的预防作用。综上所述，天scoparone通过增强线粒体自噬来阻断NLRP3炎性小体的激活，显示出强大的抗炎作用，这突出了治疗炎性小体相关疾病的潜在作用机制，有待进一步的临床研究。
Recent evidence shows that targeting NLRP3 inflammasome activation is an important means to treat inflammasome-driven diseases. Scoparone, a natural compound isolated from the Chinese herbArtemisia capillarisThunb, has anti-inflammatory activity. In this study we investigated the effect of scoparone on NLRP3 inflammasome activation in inflammatory diseases. In LPS-primed, ATP or nigericin-stimulated mouse macrophage J774A.1 cells and bone marrow-derived macrophages (BMDMs), pretreatment with scoparone (50 μM) markedly restrained canonical and noncanonical NLRP3 inflammasome activation, evidenced by suppressed caspase-1 cleavage, GSDMD-mediated pyroptosis, mature IL-1β secretion and the formation of ASC specks. We then conducted a transcriptome analysis in scoparone-pretreated BMDMs, and found that the differentially expressed genes were significantly enriched in mitochondrial reactive oxygen species (ROS) metabolic process, mitochondrial translation and assembly process, as well as in inflammatory response. We demonstrated in J774A.1 cells and BMDMs that scoparone promoted mitophagy, a well-characterized mechanism to control mitochondrial quality and reduce ROS production and subsequent NLRP3 inflammasome activation. Mitophagy blockade by 3-methyladenine (3-MA, 5 mM) reversed the protective effects of scoparone on mitochondrial damage and inflammation in the murine macrophages. Moreover, administration of scoparone (50 mg/kg) exerted significant preventive effects via inhibition of NLRP3 activation in mouse models of bacterial enteritis and septic shock. Collectively, scoparone displays potent anti-inflammatory effects via blocking NLRP3 inflammasome activation through enhancing mitophagy, highlighting a potential action mechanism in treating inflammasome-related diseases for further clinical investigation.