Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

The novel small-molecule TPN10456 inhibits Th17 cell differentiation and protects against experimental autoimmune encephalomyelitis

Cellular & Molecular Immunology volume 17, pages 1290–1293 (2020)Cite this article

Subjects

Multiple sclerosis (MS) is a predominantly T-cell-mediated autoimmune inflammatory disease of the central nervous system (CNS) characterized by multifocal areas of immune cell infiltration, demyelination, axonal damage, and disruption of neuronal signal.1,2 It is now widely accepted that MS is a heterogeneous, multifactorial disease influenced by genetic, epigenetic, and environmental factors.3 Now, subsequent studies have identified and highlighted an important pathogenic role for Th17 cells in autoimmunity, a kind of CD4+ T-cell subset that secrete signature cytokine interleukin IL-17A.4,5 However, the treatment for MS still remains a great challenge. Thus, the current prompted us to find a more effective disease-modifying treatment. Here, we found that small-molecule TPN10456 potently suppressed Th17 cell differentiation. Interestingly, TPN10456 inhibited pathogenic Th17 cells differentiation, but not conventional Th17 cells. Meanwhile, TPN10456 also inhibited human Th17 cells differentiation in vitro. Moreover, compared with the vehicle group, TPN10456-treated EAE mice showed less severe EAE symptoms, including lower clinical scores, reduced inflammatory cells infiltration, and less extensive demyelination in CNS. These results suggest that TPN10456 may represent a promising therapeutic agent for the treatment of MS.

Next, we wondered whether TPN10456 could confer protection against MS. We first examined the effects of TPN10456 in EAE mice, a widely used typical Th17-mediated autoimmune disease animal model.7,8 Our results showed TPN10456 displayed a slight but statistically beneficial effect in EAE mice at 30 mg/kg. 100 mg/kg TPN10456 can markedly inhibit the disease severity of EAE and reduce disease incidence compared with the vehicle group. The clinical symptoms of EAE mice were alleviated obviously as the dose of TPN10456 increases (Fig. 1e–h). In brief, TPN10456 not only significantly reduced the peak severity and cumulative clinical score of EAE in a dose-dependent manner but also delayed the onset and reduced disease incidence.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Ciccarelli, O. et al. Pathogenesis of multiple sclerosis: insights from molecular and metabolic imaging. Lancet Neurol. 13, 807–822 (2014).

    Article  CAS  Google Scholar 

  2. Filippi, M. et al. Association between pathological and MRI findings in multiple sclerosis. Lancet Neurol. 18, 198–210 (2019).

    Article  Google Scholar 

  3. Thompson, A. J., Baranzini, S. E., Geurts, J., Hemmer, B. & Ciccarelli, O. Multiple sclerosis. Lancet 391, 1622–1636 (2018).

    Article  Google Scholar 

  4. Xiao, F. et al. Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjogren’s syndrome. Cell. Mol. Immunol. 14, 924–934 (2017).

    Article  CAS  Google Scholar 

  5. Lee, Y. et al. Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 13, 991–999 (2012).

    Article  CAS  Google Scholar 

  6. Wu, B. et al. RAS P21 protein activator 3 (RASA3) specifically promotes pathogenic T helper 17 cell generation by repressing T-helper-2-cell-biased programs. Immunity 49, 886–898.e5 (2018).

    Article  CAS  Google Scholar 

  7. McGinley, A. M., Edwards, S. C., Raverdeau, M. & Mills, K. H. G. Th17cells, gammadelta T cells and their interplay in EAE and multiple sclerosis. J. Autoimmun. 87, 97–108 (2018).

    Article  CAS  Google Scholar 

  8. Xu, S. & Cao, X. Interleukin-17 and its expanding biological functions. Cell. Mol. Immunol. 7, 164–174 (2010).

    Article  CAS  Google Scholar 

  9. Sonobe, Y. et al. Chronological changes of CD4(+) and CD8(+) T cell subsets in the experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Tohoku J. Exp. Med. 213, 329–339 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (32070768, 31871404, 31900658), the Strategic Priority Research Program of Chinese Academy of Sciences (No. XDA12040327), the Shanghai Municipal Science and Technology Major Project (Grant No. 2017SHZDZX01) and the State Key Laboratory of Drug Research.

Author information

Author notes

  1. These authors contributed equally: Cuixia Yang, Jie Lv, Xiangrui Jiang

Authors and Affiliations

  1. Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China

    Cuixia Yang, Jie Lv, Zhenglong Xiang, Ran Gong, Jiahua Xing, Guangyu Liu, Ling Xie, Kandireya Saimaier & Changsheng Du

  2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China

    Xiangrui Jiang, Yan Zhang & Jingshan Shen

  3. CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China

    Xiangrui Jiang, Yan Zhang & Jingshan Shen

  4. College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450001, China

    Junjian Wang

  5. Tongji Hospital of Tongji University branch, Tongji University, Shanghai, 200092, China

    Hu Shen & Juping Pan

Authors
  1. Cuixia Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiangrui Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhenglong Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ran Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiahua Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guangyu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ling Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kandireya Saimaier
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Junjian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hu Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Juping Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jingshan Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Changsheng Du
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Design and experimentation: C.Y., J.L., X.J., Z.X., R.G., J.X., G.L., L.X., K.S., J.W., H.S., J.P.; supervision: C.D. and J.S.; and manuscript writing: C.Y., J.L., X.J., and C.D.

Corresponding authors

Correspondence to Jingshan Shen or Changsheng Du.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, C., Lv, J., Jiang, X. et al. The novel small-molecule TPN10456 inhibits Th17 cell differentiation and protects against experimental autoimmune encephalomyelitis. Cell Mol Immunol 17, 1290–1293 (2020). https://doi.org/10.1038/s41423-020-00566-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-020-00566-8

This article is cited by

Search

Advanced search

Quick links