Neuroinflammation leads to tissue injury causing many of the clinical symptoms of Multiple Sclerosis, an autoimmune disorder of the central nervous system (CNS). While T cells, specifically T_h1 and T_h17 cells, are the ultimate effectors of this disease, dendritic cells (DCs) mediate T cell polarization, activation, etc. In our previous study, Apigenin, a natural flavonoid, has been shown to reduce EAE disease severity through amelioration of demyelination in the CNS as well as the sequestering of DCs and other myeloid cells in the periphery. Here, we show that Apigenin exerts its effects possibly through shifting DC modulated T cell responses from T_h1 and T_h17 type towards T_reg directed responses evident through the decrease in T-bet, IFN-γ (T_h1), IL-17 (T_h17) and increase in IL-10, TGF-β and FoxP3 (T_reg) expression in cells from both normal human donors and EAE mice. RelB, an NF-κβ pathway protein is central to DC maturation, its antigen presentation capabilities and DC-mediated T cell activation. Apigenin reduced mRNA and protein levels of RelB and also reduced its nuclear translocation. Additionally, siRNA-mediated silencing of RelB further potentiated the RelB-mediated effects of Apigenin thus confirming its role in Apigenin directed regulation of DC biology. These results provide key information about the molecular events controlled by Apigenin in its regulation of DC activity marking its potential as a therapy for neuroinflammatory disease.

Graphical Abstract

神经炎症导致组织损伤，导致多发性硬化症的许多临床症状，多发性硬化症是一种中枢神经系统 (CNS) 的自身免疫性疾病。虽然 T 细胞，特别是 T _h 1 和 T _h 17 细胞是这种疾病的最终效应物，但树突状细胞 (DC) 介导 T 细胞极化、激活等。在我们之前的研究中，芹菜素是一种天然类黄酮，已被证明通过改善 CNS 中的脱髓鞘以及隔离外周的 DCs 和其他骨髓细胞来降低 EAE 疾病的严重程度。在这里，我们表明芹菜素可能通过将 DC 调节的 T 细胞反应从 T _h 1 和 T _h 17 类型转移到 T _{reg来发挥其作用。}通过降低T -bet、IFN- γ ( _Th 1) 、 IL-17 ( _Th 17) 和增加 IL-10、TGF-β 和 FoxP3 (T _reg) 在来自正常人类供体和 EAE 小鼠的细胞中表达。RelB 是一种 NF-κβ 通路蛋白，对 DC 成熟、其抗原呈递能力和 DC 介导的 T 细胞活化至关重要。芹菜素降低了 RelB 的 mRNA 和蛋白质水平，也降低了其核转位。此外，siRNA 介导的 RelB 沉默进一步增强了芹菜素的 RelB 介导的作用，从而证实了其在芹菜素定向调节 DC 生物学中的作用。这些结果提供了关于芹菜素在调节 DC 活性中控制的分子事件的关键信息，标志着其作为神经炎性疾病治疗的潜力。

图形概要