Abstract
Inhibition of NLRP3 inflammasome activation produces potent therapeutic effects in a wide array of inflammatory diseases. Bergapten (BeG), a furocoumarin phytohormone present in many herbal medicines and fruits, exibits anti-inflammatory activity. In this study we characterized the therapeutic potential of BeG against bacterial infection and inflammation-related disorders, and elucidated the underlying mechanisms. We showed that pre-treatment with BeG (20 μM) effectively inhibited NLRP3 inflammasome activation in both lipopolysaccharides (LPS)-primed J774A.1 cells and bone marrow-derived macrophages (BMDMs), evidenced by attenuated cleaved caspase-1 and mature IL-1β release, as well as reduced ASC speck formation and subsequent gasdermin D (GSDMD)-mediated pyroptosis. Transcriptome analysis revealed that BeG regulated the expression of genes involved in mitochondrial and reactive oxygen species (ROS) metabolism in BMDMs. Moreover, BeG treatment reversed the diminished mitochondrial activity and ROS production after NLRP3 activation, and elevated the expression of LC3-II and enhanced the co-localization of LC3 with mitochondria. Treatment with 3-methyladenine (3-MA, 5 mM) reversed the inhibitory effects of BeG on IL-1β, cleaved caspase-1 and LDH release, GSDMD-N formation as well as ROS production. In mouse model of Escherichia coli-induced sepsis and mouse model of Citrobacter rodentium-induced intestinal inflammation, pre-treatment with BeG (50 mg/kg) significantly ameliorated tissue inflammation and injury. In conclusion, BeG inhibits NLRP3 inflammasome activation and pyroptosis by promoting mitophagy and maintaining mitochondrial homeostasis. These results suggest BeG as a promising drug candidate for the treatment of bacterial infection and inflammation-related disorders.
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Acknowledgements
This work was supported by the National Natural Science Foundation (NNSF) of China (Nos. 82001663), Young Elite Scientists Sponsorship Program by China Association for Science and Technology (No. 2020-QNRC1-03), and Joint Fund of Beijing University of Traditional Chinese Medicine and USANA. We are grateful to Prof. Feng Shao (National Institute of Biological Sciences, Beijing, China) for providing iBMDM, Prof. Chen Dong (Tsinghua University, Beijing, China) for providing C. rodentium.
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YW, XJ and ALX conceived the study; TL, WDF, JYW and FX performed the experiments. LDK, XJW, XL and RL contributed to the interpretation of results. TL and XJ wrote the manuscript and YW and ALX made pivotal revisions; YJC provided computational analysis; YW and ALX supervised the project.
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Luo, T., Jia, X., Feng, Wd. et al. Bergapten inhibits NLRP3 inflammasome activation and pyroptosis via promoting mitophagy. Acta Pharmacol Sin 44, 1867–1878 (2023). https://doi.org/10.1038/s41401-023-01094-7
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DOI: https://doi.org/10.1038/s41401-023-01094-7
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