PMID- 36522512 OWN - NLM STAT- MEDLINE DCOM- 20230524 LR - 20230525 IS - 1745-7254 (Electronic) IS - 1671-4083 (Print) IS - 1671-4083 (Linking) VI - 44 IP - 6 DP - 2023 Jun TI - Scoparone suppresses mitophagy-mediated NLRP3 inflammasome activation in inflammatory diseases. PG - 1238-1251 LID - 10.1038/s41401-022-01028-9 [doi] AB - 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 muM) markedly restrained canonical and noncanonical NLRP3 inflammasome activation, evidenced by suppressed caspase-1 cleavage, GSDMD-mediated pyroptosis, mature IL-1beta 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. CI - (c) 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society. FAU - Feng, Wan-di AU - Feng WD AD - Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Wang, Yao AU - Wang Y AD - Department of Immunology, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China. AD - National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for Metabolic Diseases, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Luo, Tong AU - Luo T AD - Department of Immunology, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Jia, Xin AU - Jia X AD - Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Cheng, Cui-Qin AU - Cheng CQ AD - Department of Immunology, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Wang, Hao-Jia AU - Wang HJ AD - Department of Immunology, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Zhang, Mei-Qi AU - Zhang MQ AD - Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Li, Qi-Qi AU - Li QQ AD - Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Wang, Xue-Jiao AU - Wang XJ AD - Department of Immunology, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Li, Yi-Ying AU - Li YY AD - Department of Immunology, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Wang, Jin-Yong AU - Wang JY AD - Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Huang, Guang-Rui AU - Huang GR AD - Department of Immunology, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Wang, Ting AU - Wang T AD - Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. AD - National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for Metabolic Diseases, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Xu, An-Long AU - Xu AL AD - Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. xuanlong@bucm.edu.cn. AD - Department of Immunology, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China. xuanlong@bucm.edu.cn. AD - National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for Metabolic Diseases, Beijing University of Chinese Medicine, Beijing, 100029, China. xuanlong@bucm.edu.cn. LA - eng PT - Journal Article DEP - 20221215 PL - United States TA - Acta Pharmacol Sin JT - Acta pharmacologica Sinica JID - 100956087 RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - H5841PDT4Y (scoparone) RN - 0 (Reactive Oxygen Species) RN - 0 (Anti-Inflammatory Agents) RN - 0 (Interleukin-1beta) RN - 0 (Lipopolysaccharides) RN - 0 (Nlrp3 protein, mouse) SB - IM MH - Animals MH - Mice MH - *Inflammasomes/metabolism MH - *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - Mitophagy MH - Reactive Oxygen Species/metabolism MH - Anti-Inflammatory Agents/pharmacology/therapeutic use MH - Interleukin-1beta/metabolism MH - Lipopolysaccharides/pharmacology MH - Mice, Inbred C57BL PMC - PMC10203299 OTO - NOTNLM OT - 3-methyladenine OT - IL-1beta OT - NLRP3 inflammasome OT - inflammatory disease OT - mitophagy OT - scoparone COIS- The authors declare no competing interests. EDAT- 2022/12/16 06:00 MHDA- 2023/05/24 06:42 PMCR- 2024/06/01 CRDT- 2022/12/15 23:35 PHST- 2022/07/18 00:00 [received] PHST- 2022/11/07 00:00 [accepted] PHST- 2024/06/01 00:00 [pmc-release] PHST- 2023/05/24 06:42 [medline] PHST- 2022/12/16 06:00 [pubmed] PHST- 2022/12/15 23:35 [entrez] AID - 10.1038/s41401-022-01028-9 [pii] AID - 1028 [pii] AID - 10.1038/s41401-022-01028-9 [doi] PST - ppublish SO - Acta Pharmacol Sin. 2023 Jun;44(6):1238-1251. doi: 10.1038/s41401-022-01028-9. Epub 2022 Dec 15.