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).

中文翻译：

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TPN10475 通过促进 TGF-β 信号转导抑制效应 T 淋巴细胞激活并减弱实验性自身免疫性脑脊髓炎发病机制

摘要

多发性硬化症 (MS) 是一种由免疫细胞介导的中枢神经系统 (CNS) 炎症性脱髓鞘疾病，其中自身反应性 CD4 ⁺ T 细胞被认为是该疾病发病机制的主要驱动因素。在本研究中，我们旨在探讨青蒿素衍生物TPN10475是否可以缓解实验性自身免疫性脑脊髓炎（EAE）（一种常用的MS动物模型）及其可能的机制。^{TPN10475有效抵抗TCR刺激引起的TGF-β信号转导的降低，抑制体外效应CD4 +} T细胞的活化和功能，并限制致病性Th1和Th17细胞的分化。研究还发现，它可以通过减少自身反应性辅助 T 淋巴细胞的外周激活驱动，抑制炎症细胞迁移到 CNS 来减轻 EAE，从而负向调节 EAE 的炎症反应。上述结果提示TGF-β信号转导的上调可能为MS发病机制的研究提供新思路，并对自身免疫性疾病治疗药物的研发具有积极意义。

图形概要

TPN10475在TCR刺激下促进TGF-β信号传导，限制效应CD4 ⁺ T细胞的增殖和活化，抑制致病性Th1和Th17细胞的分化，负向调节炎症反应并抑制炎症细胞向CNS迁移，从而缓解EAE。该人物是通过 Biorender.com 创建的（协议号：ME25MXMB52）。