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Triptolide induces PANoptosis in macrophages and causes organ injury in mice

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Abstract

Macrophages represent the first lines of innate defense against pathogenic infections and are poised to undergo multiple forms of regulated cell death (RCD) upon infections or toxic stimuli, leading to multiple organ injury. Triptolide, an active compound isolated from Tripterygium wilfordii Hook F., possesses various pharmacological activities including anti-tumor and anti-inflammatory effects, but its applications have been hampered by toxic adverse effects. It remains unknown whether and how triptolide induces different forms of RCD in macrophages. In this study, we showed that triptolide exhibited significant cytotoxicity on cultured macrophages in vitro, which was associated with multiple forms of lytic cell death that could not be fully suppressed by any one specific inhibitor for a single form of RCD. Consistently, triptolide induced the simultaneous activation of pyroptotic, apoptotic and necroptotic hallmarks, which was accompanied by the co-localization of ASC specks respectively with RIPK3 or caspase-8 as well as their interaction with each other, indicating the formation of PANoptosome and thus the induction of PANoptosis. Triptolide-induced PANoptosis was associated with mitochondrial dysfunction and ROS production. PANoptosis was also induced by triptolide in mouse peritoneal macrophages in vivo. Furthermore, triptolide caused kidney and liver injury, which was associated with systemic inflammatory responses and the activation of hallmarks for PANoptosis in vivo. Collectively, our data reveal that triptolide induces PANoptosis in macrophages in vitro and exhibits nephrotoxicity and hepatotoxicity associated with induction of PANoptosis in vivo, suggesting a new avenue to alleviate triptolide’s toxicity by harnessing PANoptosis.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82274167, 81873064 and 81773965), the Funding of Science and Technology Projects in Guangzhou (202201020083), and the Medical Scientific Research Foundation of Guangdong Province, China (B2021116). We also thank Prof. Yong-tang Zheng (Kunming Institute of Zoology, Chinese Academy of Sciences) for his kindly help in this study.

Funding

This work was supported by the National Natural Science Foundation of China (82274167, 81873064 and 81773965), the Funding of Science and Technology Projects in Guangzhou (202201020083), and the Medical Scientific Research Foundation of Guangdong Province, China (B2021116).

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  1. Hong-Rui Zhang, Ya-Ping Li and Zi-Jian Shi have contributed equally to this work.

Authors and Affiliations

  1. Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China

    Hong-Rui Zhang, Ya-Ping Li, Qi-Qi Liang, Si-Yuan Chen, Yi-Ping You, Tao Yuan, Rong Xu, Dong-Yun Ouyang & Xian-Hui He

  2. Department of Fetal Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China

    Zi-Jian Shi & Qing-Bing Zha

  3. Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China

    Li-Hui Xu

  4. Department of Clinical Laboratory, The Fifth Affiliated Hospital of Jinan University, Heyuan, 517000, China

    Hong-Rui Zhang, Qing-Bing Zha & Xian-Hui He

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Contributions

H.R.Z., Y.P.L., Z.J.S., Q.Q.L., and S.Y.C. performed the in vitro research. Y.P.Y., T.Y., R.X., and L.H.X. carried out the animal experiments. X.H.H. and Q.B.Z. conceived and supervised the project. H.R.Z. and X.H.H. designed this study. H.R.Z. and X.H.H. analyzed the data. H.R.Z., X.H.H. and D.Y.O. prepared and edited the manuscript. All authors approved the submission.

Corresponding authors

Correspondence to Dong-Yun Ouyang, Qing-Bing Zha or Xian-Hui He.

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Animal experiments were performed with the approval of and in compliance with the guidelines for the care and use of animals approved by the Committee on the Ethics of Animal Experiments of Jinan University.

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Zhang, HR., Li, YP., Shi, ZJ. et al. Triptolide induces PANoptosis in macrophages and causes organ injury in mice. Apoptosis 28, 1646–1665 (2023). https://doi.org/10.1007/s10495-023-01886-6

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