Shao Hefang, Fan Weijiao, Tang Yang
Center for Reproductive Medicine, Department of Pediatrics, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Gen Physiol Biophys. 2023 Jan;42(1):13-24. doi: 10.4149/gpb_2022048.
Guillain-Barré syndrome (GBS) is an acute immune-mediated paralytic neuropathy with variable disease course and outcome. In this study, we aimed to investigate the therapeutic effects of celastrol on GBS and uncover its underlying mechanisms. Experimental autoimmune neuritis (EAN) is a typical animal model for GBS, and thus an EAN rat model was established with the injection of celastrol or/and LPS. We assessed the body weights and EAN clinical scores of rats. HE staining, flow cytometry, RT-qPCR, and Western blotting were respectively employed to measure pathological damage, proportions of cells (Th1, Th17, and Treg), Th1/Th17 cell differentiation-related mRNAs (IFN-γ, TBX21, IL-18, RORγT, IL-17, and IL-23) and TLR4/NF-κB/STAT3 pathway-related proteins (TLR4, NF-κB, p-NF-κB, STAT3, and p-STAT3). We found that celastrol attenuated clinical symptoms and pathological damage of GBS in EAN rats. Moreover, celastrol down-regulated Th1 and Th17 cell proportions, and the levels of IFN-γ, TBX21, IL-18, RORγT, IL-17, and IL-23 in EAN rats. Meanwhile, the levels of TLR4, p-NF-κB, and p-STAT3 were decreased by celastrol. Taken together, celastrol could restrain Th1/Th17 cell differentiation through inhibition of the TLR4/NF-κB/STAT3 pathway in EAN rats. Our findings suggest that celastrol may exert therapeutic effects on GBS by suppressing TLR4/NF-κB/STAT3 pathway-mediated Th1/Th17 cell differentiation.
吉兰-巴雷综合征（GBS）是一种急性免疫介导的麻痹性神经病，病程和预后各异。在本研究中，我们旨在研究雷公藤红素对GBS的治疗作用并揭示其潜在机制。实验性自身免疫性神经炎（EAN）是GBS的典型动物模型，因此通过注射雷公藤红素或/和脂多糖建立了EAN大鼠模型。我们评估了大鼠的体重和EAN临床评分。分别采用苏木精-伊红（HE）染色、流式细胞术、逆转录-定量聚合酶链反应（RT-qPCR）和蛋白质免疫印迹法来测量病理损伤、细胞比例（Th1、Th17和调节性T细胞（Treg））、Th1/Th17细胞分化相关的信使核糖核酸（mRNA）（γ-干扰素（IFN-γ）、T-box蛋白21（TBX21）、白细胞介素-18（IL-18）、维甲酸相关孤核受体γt（RORγT）、白细胞介素-17（IL-17）和白细胞介素-23（IL-23））以及Toll样受体4（TLR4）/核因子κB（NF-κB）/信号转导子和转录激活子3（STAT3）通路相关蛋白（TLR4、NF-κB、磷酸化NF-κB（p-NF-κB）、STAT3和磷酸化STAT3（p-STAT3））。我们发现雷公藤红素减轻了EAN大鼠GBS的临床症状和病理损伤。此外，雷公藤红素下调了EAN大鼠中Th1和Th17细胞的比例以及IFN-γ、TBX21、IL-18、RORγT、IL-17和IL-23的水平。同时，雷公藤红素降低了TLR4、p-NF-κB和p-STAT3的水平。综上所述，雷公藤红素可通过抑制EAN大鼠的TLR4/NF-κB/STAT3通路来抑制Th1/Th17细胞分化。我们的研究结果表明，雷公藤红素可能通过抑制TLR4/NF-κB/STAT3通路介导的Th1/Th17细胞分化对GBS发挥治疗作用。
