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Unexpected mechanism of colitis amelioration by artesunate, a natural product from Artemisia annua L.

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Abstract

Background

Artemisinin and its derivatives are known to exert immunosuppressive effects through modulating adaptive immunity. We investigated a novel role of artesunate in regulating innate immunity, including both macrophages (MΦ) and dendritic cells (DCs), which are known to involve in DSS-induced colitis.

Methods

Effects of artesunate on innate immunity were extensively evaluated, both in vivo using DSS-colitis model with WT and T cell-deficient RAG mice (RAG−/−) and in vitro using cell culture models, including in-depth analyses of MΦ/DC apoptosis and cytokine expression by flow cytometry, Western blot, or immunohistology.

Results

Unexpectedly, artesunate significantly ameliorated the DSS colitis of both WT and RAG1−/− mice with similar potency, suggesting a mechanism that involves primarily innate rather than adaptive immunity. In vivo mechanistic studies revealed that artesunate markedly induced apoptosis of lamina propria MΦs and DCs and suppressed mucosal TNF-α and IL-12p70 in DSS-colitis. In vitro, artesunate potently induced a dose- and time-dependent apoptosis of murine bone marrow-derived DCs and human THP-1 MΦs, through the caspases-9-mediated intrinsic pathway. Artesunate significantly decreased the secretion of IL-12p40/70 by DCs and TNF-α by MΦs. Furthermore, a combination of artesunate with an immunomodulator (methotrexate/triptolide/azathioprine) exhibited superior potency in promoting apoptosis of MΦs than any individual drug alone.

Conclusions

The immunomodulatory mechanism of artesunate in colitis involves a novel and potent induction of the intrinsic apoptosis pathway of proliferating MΦs and DCs and suppression of IL-12 and TNF-α. Artemisinin and its derivatives are promising new therapeutic alternatives for IBD, either alone or in combination with other immunomodulators.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81370509).

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Author notes

  1. Weili Sun

    Present address: Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC, Canada

  2. Xiao Han & Jianghong Wu

    Present address: Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

  3. Weili Sun and Xiao Han contributed equally to this work.

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Shandong Zhong Road, Shanghai, 200001, China

    Weili Sun, Xiao Han, Siyuan Wu, Jianghong Wu & Chuanhua Yang

  2. Department of Medicine, GI Division, Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 918, Baltimore, MD, 21205, USA

    Xuhang Li

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  1. Weili Sun
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Correspondence to Chuanhua Yang or Xuhang Li.

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Sun, W., Han, X., Wu, S. et al. Unexpected mechanism of colitis amelioration by artesunate, a natural product from Artemisia annua L.. Inflammopharmacol 28, 851–868 (2020). https://doi.org/10.1007/s10787-019-00678-2

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  • DOI: https://doi.org/10.1007/s10787-019-00678-2

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