Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China; CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia, Medica, Chinese Academy of Sciences, Shanghai, China.
Int Immunopharmacol. 2023 Oct;123:110787. doi: 10.1016/j.intimp.2023.110787. Epub 2023 Aug 15.
Multiple sclerosis (MS) is one of the most common autoimmune diseases of central nervous system (CNS) demyelination. Experimental autoimmune encephalomyelitis (EAE) is the most classic animal model for simulating the onset of clinical symptoms in MS. Previous research has reported the anti-inflammatory effects of artemisinin on autoimmune diseases. In our study, we identified a novel small molecule, TPN10518, an artemisinin derivative, which plays a protective role on the EAE model. We found that TPN10518 reduced CNS inflammatory cell infiltration and alleviated clinical symptoms of EAE. In addition, TPN10518 downregulated the production of Th1 and Th17 cells in vivo and in vitro, and decrease the levels of related chemokines. RNA-seq assay combined with the experimental results demonstrated that TPN10518 lowered the mRNA and protein levels of the AP1 subunits c-Fos and c-Jun in EAE mice. It was further confirmed that TPN10518 was dependent on AP1 to inhibit the differentiation of Th1 and Th17 cells. The results suggest that TPN10518 reduces the production of Th1 and Th17 cells through inhibition of AP1 to alleviate the severity of EAE disease. It is expected to be a potential drug for the treatment of MS.
多发性硬化症（MS）是最常见的中枢神经系统（CNS）脱髓鞘自身免疫性疾病之一。实验性自身免疫性脑脊髓炎（EAE）是模拟 MS 临床症状发作的最经典动物模型。先前的研究报道了青蒿素对自身免疫性疾病的抗炎作用。在我们的研究中，我们鉴定了一种新型小分子 TPN10518，它是青蒿素的衍生物，对 EAE 模型具有保护作用。我们发现 TPN10518 减少了中枢神经系统炎症细胞浸润并缓解了 EAE 的临床症状。此外，TPN10518 在体内和体外下调了 Th1 和 Th17 细胞的产生，并降低了相关趋化因子的水平。RNA-seq 分析与实验结果相结合表明，TPN10518 降低了 EAE 小鼠中 AP1 亚基 c-Fos 和 c-Jun 的 mRNA 和蛋白水平。进一步证实 TPN10518 依赖于 AP1 抑制 Th1 和 Th17 细胞的分化。结果表明，TPN10518 通过抑制 AP1 减少 Th1 和 Th17 细胞的产生，从而缓解 EAE 疾病的严重程度。它有望成为治疗 MS 的潜在药物。
