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Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation

Cellular & Molecular Immunology volume 13, pages 379–390 (2016)Cite this article

Abstract

We previously reported that SM934, a water-soluble artemisinin derivative, was a viable treatment in murine lupus models. In the current study, we further investigated the therapeutic effects of a modified dosage regimen of SM934 on lupus-prone MRL/lpr mice and explored its effects on B cell responses, a central pathogenic event in systemic lupus erythematosus (SLE). When orally administered twice-daily, SM934 significantly prolonged the life-span of MRL/lpr mice, ameliorated the lymphadenopathy symptoms and decreased the levels of serum anti-nuclear antibodies (ANAs) and of the pathogenic cytokines IL-6, IL-10 and IL-21. Furthermore, SM934 treatment restored the B-cell compartment in the spleen of MRL/lpr mice by increasing quiescent B cell numbers, maintaining germinal center B-cell numbers, decreasing activated B cell numbers and reducing plasma cell (PC) numbers. Ex vivo, SM934 suppressed the Toll-like receptor (TLR)-triggered activation and proliferation of B cells, as well as antibody secretion. Moreover, the present study demonstrated that SM934 interfered with the B-cell intrinsic pathway by downregulating TLR7/9 mRNA expression, MyD88 protein expression and NF-κB phosphorylation. In human peripheral blood mononuclear cells (PBMCs), consistent with the results in MRL/lpr mice, SM934 inhibited TLR-associated B-cell activation and PC differentiation. In conclusion, a twice daily dosing regimen of SM934 had therapeutic effects on lupus-prone MRL/lpr mice by suppressing B cell activation and plasma cell formation.

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Acknowledgements

This work was supported by grants from the National Science Fair Committee (NSFC), China (No. 81273524, 81322049), National Science & Technology Major Project ‘New Drug Creation and Manufacturing Program’, China (2014ZX09101002) and National Key Basic Research Programme (973 Programme, 2014CB541906). We are also grateful to Dr Hou Lifei who kindly contributed to the manuscript revision.

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Author notes

  1. Dr JP Zuo, Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. E-mail: jpzuo@simm.ac.cn

  2. Dr W Tang, Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. E-mail: tangwei@simm.ac.cn

Authors and Affiliations

  1. Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Yanwei Wu, Shijun He, Luyao Zhang, Xiaoqian Yang, Fenghua Zhu, Peilan He, Wei Tang & Jianping Zuo

  2. Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Bingxin Bai, Lu Xue, Zemin Lin & Jianping Zuo

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Wu, Y., He, S., Bai, B. et al. Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation. Cell Mol Immunol 13, 379–390 (2016). https://doi.org/10.1038/cmi.2015.13

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