Abstract
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 herb Artemisia capillaris Thunb, 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.
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Acknowledgements
This work was supported by the National Natural Science Foundation (NNSF) of China (Nos. 91942301, 31900661 and 82001663), Young Elite Scientists Sponsorship Program by China Association for Science and Technology (No. 2020-QNRC1-03), National Key Research and Development Project (No. 2019YFC1710104), and Joint Fund of Beijing University of Traditional Chinese Medicine and USANA. We thank Dr. Chen Dong for the C. rodentium. We are indebted to all individuals who participated in or helped with this research project.
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ALX conceived the study; WDF and TL designed and performed most of the experiments and collected results. WDF analyzed, interpreted results and wrote the manuscript. YW and XJ designed research and instructed experiment. YW helped to analyze and interprete results, and revised the manuscript. CQC participated in H&E performance. HJW contributed to RNA-seq analysis. MQZ instructed article figure drawing. QQL, XJW, YYL and JYW helped to establish the animal model. GRH and TW oversaw a portion of the work and provided advice. ALX provided funding for the project, and supervised the project and revised/approved the manuscript.
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Feng, Wd., Wang, Y., Luo, T. et al. Scoparone suppresses mitophagy-mediated NLRP3 inflammasome activation in inflammatory diseases. Acta Pharmacol Sin 44, 1238–1251 (2023). https://doi.org/10.1038/s41401-022-01028-9
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DOI: https://doi.org/10.1038/s41401-022-01028-9
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