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IL-6R blockade by chikusetsusaponin IVa butyl ester inhibits Th17 cell differentiation and ameliorates collagen-induced arthritis

Cellular & Molecular Immunology volume 18, pages 1584–1586 (2021)Cite this article

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Interleukin (IL)-6 is central to the pathogenesis of rheumatoid arthritis (RA).1 IL-6 receptor (IL-6R) blockade is an effective treatment strategy for RA based on the clinical efficacy of tocilizumab. However, serious infections are the most frequent adverse events associated with long-term monotherapy with tocilizumab, an exogenous biomacromolecule.2 Novel small-molecule IL-6R inhibitors with fewer deleterious side effects could therefore have potential as RA treatments. We previously identified chikusetsusaponin IVa butyl ester (CS) as a natural small-molecule IL-6R antagonist.3 Here, we assessed the effects of CS on a mouse model of collagen-induced arthritis (CIA) to evaluate its therapeutic potential against RA. The results showed that CS ameliorated arthritis in CIA mice by inhibiting T-helper 17 (Th17) cell differentiation and could serve as a novel agent for treating RA.

Blocking IL-6R with tocilizumab induced profound repair of bone erosion.4 The numbers of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts (Fig. 1C) and the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and matrix metalloproteinase-3 (MMP3) (Fig. S2A–C) in the ankle joints were significantly lower in CIA mice treated with CS than in those treated with the vehicle. These findings were supported by the presence of relatively complete cartilage structure (Fig. S2A) and the significantly improvements in bone indices (bone mineral density [BMD], bone surface density/bone volume fraction [BS/BV], bone volume/tissue volume [BV/TV], and trabecular thickness [Tb.Th]) in CS-treated CIA mice compared with vehicle-treated CIA mice, indicating that CS ameliorated ankle joint bone erosion in CIA mice (Fig. 1D, E and Fig. S2D). Furthermore, serum levels of bovine collagen II-specific total IgG, IgG2a, and IgG2b were significantly lower in mice treated with 40 mg/kg CS than in mice treated with the vehicle (Fig. 1F).

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Acknowledgements

The authors would like to thank Professor Liwei Lu in Hong Kong University for assistance for CIA model establishment and manuscript revision, and Professor  You Yang at East China University of Science and Technology for synthesizing CS. This work was supported by a grant from the National Natural Science Foundation of China (No. 81773973).

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Authors and Affiliations

  1. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China

    Jie Yang, Yuanyuan Ling, Di Hua, Chenglei Zhao, Xiaoyan Sun, Xueting Cai, Jiao Chen, Chunping Hu & Peng Cao

  2. College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China

    Peng Cao

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  1. Jie Yang
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  2. Yuanyuan Ling
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  3. Di Hua
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Contributions

Study conception and design: P.C., J.Y., C.H. Acquisition of data: J.Y., C.Z., Y.L., D.H. Analysis and interpretation of data: J.Y., Y.L., D.H. Paper writing: J.Y. Manuscript editing and revision: P.C., X.S., X.C., J.C.

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Correspondence to Peng Cao.

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Yang, J., Ling, Y., Hua, D. et al. IL-6R blockade by chikusetsusaponin IVa butyl ester inhibits Th17 cell differentiation and ameliorates collagen-induced arthritis. Cell Mol Immunol 18, 1584–1586 (2021). https://doi.org/10.1038/s41423-021-00651-6

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