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

Weili Sun, Xiao Han, Siyuan Wu, Jianghong Wu, Chuanhua Yang, Xuhang Li

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)851-868
Number of pages18
JournalInflammopharmacology
Volume28
Issue number4
DOIs
StatePublished - Aug 1 2020

Keywords

  • Apoptosis
  • Artesunate
  • DSS-colitis
  • Inflammatory bowel disease
  • Innate immune

ASJC Scopus subject areas

  • Immunology
  • Pharmacology
  • Pharmacology (medical)

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