Skip to main content

Advertisement

SpringerLink
Log in

TPN10475 Constrains Effector T Lymphocytes Activation and Attenuates Experimental Autoimmune Encephalomyelitis Pathogenesis by Facilitating TGF-β Signal Transduction

  • Research
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) mediated by immune cells, in which auto-reactive CD4+ T cells have been implicated as a major driver in the pathogenesis of the disease. In this study, we aimed to investigate whether the artemisinin derivative TPN10475 could alleviate experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of MS and its possible mechanisms. TPN10475 effectively resisted the reduction of TGF-β signal transduction induced by TCR stimulation, suppressed the activation and function of effector CD4+ T cells in vitro, and restricted the differentiation of pathogenic Th1 and Th17 cells. It was also found to negatively regulate the inflammatory response in EAE by reducing the peripheral activation drive of auto-reactive helper T lymphocytes, inhibiting the migration of inflammatory cells into the CNS to attenuate EAE. The above results suggested that the upregulation of TGF-β signal transduction may provide new ideas for the study of MS pathogenesis and have positive implications for the development of drugs for the treatment of autoimmune diseases.

Graphical Abstract

TPN10475 promotes TGF-β signaling under TCR stimulation, restricts the proliferation and activation of effector CD4+ T cells, inhibits the differentiation of pathogenic Th1 and Th17 cells, negatively regulates the inflammatory response and suppresses the migration of inflammatory cells to the CNS, thereby alleviating EAE. The figure was created with Biorender.com (Agreement number: ME25MXMB52).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data Availability

The material and data used to support the findings of the current study are available from the corresponding author on reasonable request.

References

  • Bierie B, Chung CH, Parker JS, Stover DG, Cheng N, Chytil A, Aakre M, Shyr Y, Moses HL (2009) Abrogation of TGF-beta signaling enhances chemokine production and correlates with prognosis in human breast cancer. J Clin Invest 119:1571–1582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bright JJ, Sriram S (1998) TGF-beta inhibits IL-12-induced activation of Jak-STAT pathway in T lymphocytes. J Immunol (Baltimore Md: 1950) 161:1772–1777

    Article  CAS  Google Scholar 

  • Cekanaviciute E, Dietrich HK, Axtell RC, Williams AM, Egusquiza R, Wai KM, Koshy AA, Buckwalter MS (2014) Astrocytic TGF-beta signaling limits inflammation and reduces neuronal damage during central nervous system Toxoplasma infection. J Immunol 193:139–149

    Article  CAS  PubMed  Google Scholar 

  • Chapman NM, Boothby MR, Chi H (2020) Metabolic coordination of T cell quiescence and activation. Nat Rev Immunol 20:55–70

    Article  CAS  PubMed  Google Scholar 

  • Codarri L, Gyülvészi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B (2011) RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12:560–567

    Article  CAS  PubMed  Google Scholar 

  • Constantinescu CS, Farooqi N, O’Brien K, Gran B (2011) Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol 164:1079–1106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Correale J, Gaitan MI, Ysrraelit MC, Fiol MP (2017) Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain 140:527–546

    PubMed  Google Scholar 

  • Dendrou CA, Fugger L, Friese MA (2015) Immunopathology of multiple sclerosis. Nat Rev Immunol 15:545–558

    Article  CAS  PubMed  Google Scholar 

  • Derynck R, Budi EH (2019) Specificity, versatility, and control of TGF-beta family signaling. Sci Signal 12:eaav5183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dittel BN (2008) CD4 T cells: balancing the coming and going of autoimmune-mediated inflammation in the CNS. Brain Behav Immun 22:421–430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dobson R, Giovannoni G (2019) Multiple sclerosis - a review. Eur J Neurol 26:27–40

    Article  CAS  PubMed  Google Scholar 

  • Du C, Liu C, Kang J, Zhao G, Ye Z, Huang S, Li Z, Wu Z, Pei G (2009) MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol 10:1252–1259

    Article  CAS  PubMed  Google Scholar 

  • Duscha A et al (2020) Propionic Acid shapes the multiple sclerosis Disease Course by an Immunomodulatory mechanism. Cell 180:1067-1080e1016

    Article  CAS  PubMed  Google Scholar 

  • Feng X, Li X, Liu N, Hou N, Sun X, Liu Y (2022) Glutaminolysis and CD4(+) T-cell metabolism in autoimmunity: from pathogenesis to therapy prospects. Front Immunol 13:986847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghoreschi K et al (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467:967–971

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Gorelik L (2002) Mechanism of transforming growth factor β–induced inhibition of T helper type 1 differentiation. J Exp Med 195:1499–1505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heng AHS, Han CW, Abbott C, McColl SR, Comerford I (2022) Chemokine-Driven Migration of pro-inflammatory CD4(+) T cells in CNS autoimmune disease. Front Immunol 13:817473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hohlfeld R, Dornmair K, Meinl E, Wekerle H (2016) The search for the target antigens of multiple sclerosis, part 1: autoreactive CD4 + T lymphocytes as pathogenic effectors and therapeutic targets. Lancet Neurol 15:198–209

    Article  CAS  PubMed  Google Scholar 

  • Hoppmann N, Graetz C, Paterka M, Poisa-Beiro L, Larochelle C, Hasan M, Lill CM, Zipp F, Siffrin V (2015) New candidates for CD4 T cell pathogenicity in experimental neuroinflammation and multiple sclerosis. Brain 138:902–917

    Article  PubMed  Google Scholar 

  • Kamali AN, Noorbakhsh SM, Hamedifar H, Jadidi-Niaragh F, Yazdani R, Bautista JM, Azizi G (2019) A role for Th1-like Th17 cells in the pathogenesis of inflammatory and autoimmune disorders. Mol Immunol 105:107–115

    Article  CAS  PubMed  Google Scholar 

  • Kipp M, Nyamoya S, Hochstrasser T, Amor S (2017) Multiple sclerosis animal models: a clinical and histopathological perspective. Brain Pathol 27:123–137

    Article  PubMed  PubMed Central  Google Scholar 

  • Krishnarajah S, Becher B (2022) T(H) cells and cytokines in Encephalitogenic disorders. Front Immunol 13:822919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee PW, Severin ME, Lovett-Racke AE (2017) TGF-beta regulation of encephalitogenic and regulatory T cells in multiple sclerosis. Eur J Immunol 47:446–453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Legroux L, Arbour N (2015) Multiple sclerosis and T lymphocytes: an Entangled Story. J Neuroimmune Pharmacol 10:528–546

    Article  PubMed  PubMed Central  Google Scholar 

  • Li X, Li TT, Zhang XH, Hou LF, Yang XQ, Zhu FH, Tang W, Zuo JP (2013) Artemisinin analogue SM934 ameliorates murine experimental autoimmune encephalomyelitis through enhancing the expansion and functions of regulatory T cell. PLoS ONE 8:e74108

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu G, Jiang X, Han M, Lv J, Zhuang W, Xie L, Zhang Y, Wang C, Saimaier K, Yang J, Shen J, Li N, Du C (2022) Artemisinin derivative TPN10466 suppresses immune cell migration and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis. Cell Immunol 373:104500

    Article  CAS  PubMed  Google Scholar 

  • Luckheeram RV, Zhou R, Verma AD, Xia B (2012) CD4(+)T cells: differentiation and functions. Clin Dev Immunol 2012:925135

    Article  PubMed  PubMed Central  Google Scholar 

  • Lyons AB, Blake SJ, Doherty KV (2013) Flow cytometric analysis of cell division by dilution of CFSE and related dyes. Curr Protoc Cytom Chap 9:9 (11 11–19 11 12)

    Google Scholar 

  • Mahad DH, Trapp BD, Lassmann H (2015) Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 14:183–193

    Article  CAS  PubMed  Google Scholar 

  • Oh SA, Li MO (2013) TGF-beta: guardian of T cell function. J Immunol 191:3973–3979

    Article  CAS  PubMed  Google Scholar 

  • Olek MJ (2021) Multiple sclerosis. Ann Intern Med 174:ITC81–ITC96

    Article  PubMed  Google Scholar 

  • Sun X, Cui Y, Feng H, Liu H, Liu X (2019) TGF-beta signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity. J Exp Med 216:2819–2837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takeuchi H (2014) Midkine and multiple sclerosis. Br J Pharmacol 171:931–935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takimoto T, Wakabayashi Y, Sekiya T, Inoue N, Morita R, Ichiyama K, Takahashi R, Asakawa M, Muto G, Mori T, Hasegawa E, Saika S, Hara T, Nomura M, Yoshimura A (2010) Smad2 and Smad3 are redundantly essential for the TGF-beta-mediated regulation of regulatory T plasticity and Th1 development. J Immunol 185:842–855

    Article  CAS  PubMed  Google Scholar 

  • Tu E, Chia CPZ, Chen W, Zhang D, Park SA, Jin W, Wang D, Alegre ML, Zhang YE, Sun L, Chen W (2018) T cell receptor-regulated TGF-beta type I receptor expression determines T cell quiescence and activation. Immunity 48:745-759e746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wingerchuk DM, Carter JL (2014) Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc 89:225–240

    Article  PubMed  Google Scholar 

  • Wu Y, Tang W, Zuo J (2016) Development of artemisinin drugs in the treatment of autoimmune diseases. Sci Bull 61:37–41

    Article  CAS  Google Scholar 

  • Xu J, Liu D, Niu H, Zhu G, Xu Y, Ye D, Li J, Zhang Q (2017) Resveratrol reverses doxorubicin resistance by inhibiting epithelial-mesenchymal transition (EMT) through modulating PTEN/Akt signaling pathway in gastric cancer. J Exp Clin Cancer Res 36:19

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 28:445–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This project was supported by grants from the National Natural Science Foundation of China (32070768, 32270754).

Author information

Author notes

  1. Chun Wang and Xiangrui Jiang contributed equally to this work.

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

    Chun Wang, Jie Lv, Wei Zhuang, Ling Xie, Guangyu Liu, Kaidireya Saimaier, Sanxing Han, Changjie Shi, Qiuhong Hua, Ru Zhang & Changsheng Du

  2. University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China

    Xiangrui Jiang & Wei Zhuang

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

    Xiangrui Jiang

  4. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Wei Zhuang

Authors
  1. Chun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiangrui Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jie Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ling Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guangyu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kaidireya Saimaier
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sanxing Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Changjie Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qiuhong Hua
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ru Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Changsheng Du
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Chun Wang performed the experiments and wrote the manuscript. Xiangrui Jiang and Changsheng Du conceived the study and designed the experiment. Jie Lv, Wei Zhuang, and Ling Xie helped with data collection. Guangyu Liu, Kaidireya Saimaier, and Sanxing Han assisted in the analysis of the data. Changjie Shi, Qiuhong Hua, and Ru Zhang provided software and resources. Changsheng Du extensively and critically reviewed the manuscript. All authors participated in the study and supported the publication of the final version.

Corresponding author

Correspondence to Changsheng Du.

Ethics declarations

Ethics Approval and Consent to Participate

All experiments were conducted by Ethical Principles in Animal Experimentation and were approved by the Animal Research Ethics Committee of Tongji University (Ethics number: TJAB03320103).

Consent for Publication

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, C., Jiang, X., Lv, J. et al. TPN10475 Constrains Effector T Lymphocytes Activation and Attenuates Experimental Autoimmune Encephalomyelitis Pathogenesis by Facilitating TGF-β Signal Transduction. J Neuroimmune Pharmacol 19, 6 (2024). https://doi.org/10.1007/s11481-024-10109-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11481-024-10109-x

Keywords

Search

Navigation