Wang Dan, Lu Zhe, Zhang Hang, Jin Su-Feng, Yang Hao, Li Yun-Man, Shi Li-Yun
State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China.
Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.
CNS Neurosci Ther. 2016 Jul;22(7):558-67. doi: 10.1111/cns.12537. Epub 2016 Mar 25.
Daphnetin, a coumarin derivative extracted from Daphne odora var. marginata, has been reported to have antiinflammatory and immunosuppressive properties. Our previous study indicated that it was able to remarkably suppress the neuroinflammation and suggested its potential application in treating neuroinflammatory diseases. Multiple sclerosis (MS), a Th cell-mediated autoimmune disease, is the most common inflammatory demyelinating disease of the central nervous system (CNS). We examined whether daphnetin treatment can protect mice against experimental autoimmune encephalomyelitis (EAE), an animal model for MS.
To assess the effect of daphnetin in neuroinflammatory diseases, the EAE mice were established and treated with daphnetin at 8 mg/kg for 28 days. The severity of neuroinflammation and demyelination in the spinal cords was examined histopathologically. Infiltration of CD4(+) T cells into the CNS was assessed by immunohistochemistry, and the cytokine production was determined by ELISA. Meanwhile, the effect of daphnetin on the activity of dendritic cells (DCs) was evaluated, as assessed by DCs' capability to express surface markers, secrete cytokines, and activate naïve CD4(+) T cells. Furthermore, we explored the molecular mechanisms whereby DAPH regulated DCs' activity and thereby CD4(+) T cell responses.
The administration of daphnetin markedly alleviated the clinical symptoms of EAE and reduced the CNS inflammation and demyelination in experimental mice. Th1 and Th17 cell responses were profoundly repressed in daphnetin-treated EAE mice. Mechanistically, daphnetin treatment significantly repressed the activation, maturation, and antigen-presenting capability of DCs. NF-κB signaling was significantly reduced in daphnetin-treated DCs, along with a concomitant induction of heme oxygenase-1, a negative regulator of inflammatory signaling.
Our findings for the first time demonstrate the property of daphnetin in regulating DCs' function and subsequently Th development. Given the low or absent toxicity associated with daphnetin, our data may suggest a novel safe and effective approach to control autoimmune neuroinflammation.
瑞香素是从金边瑞香中提取的一种香豆素衍生物，据报道具有抗炎和免疫抑制特性。我们之前的研究表明，它能够显著抑制神经炎症，并提示其在治疗神经炎症性疾病方面的潜在应用。多发性硬化症（MS）是一种由Th细胞介导的自身免疫性疾病，是中枢神经系统（CNS）最常见的炎症性脱髓鞘疾病。我们研究了瑞香素治疗是否能保护小鼠免受实验性自身免疫性脑脊髓炎（EAE）的侵害，EAE是MS的一种动物模型。
为了评估瑞香素在神经炎症性疾病中的作用，建立EAE小鼠模型，并用8mg/kg的瑞香素治疗28天。通过组织病理学检查脊髓中神经炎症和脱髓鞘的严重程度。通过免疫组织化学评估CD4(+)T细胞向CNS的浸润情况，并用ELISA法测定细胞因子的产生。同时，评估瑞香素对树突状细胞（DCs）活性的影响，通过DCs表达表面标志物、分泌细胞因子和激活初始CD4(+)T细胞的能力来评估。此外，我们探讨了瑞香素调节DCs活性从而影响CD4(+)T细胞反应的分子机制。
给予瑞香素可显著减轻EAE的临床症状，并减少实验小鼠CNS的炎症和脱髓鞘。在经瑞香素治疗的EAE小鼠中，Th1和Th17细胞反应受到明显抑制。机制上，瑞香素治疗显著抑制了DCs的活化、成熟和抗原呈递能力。在经瑞香素治疗的DCs中，NF-κB信号显著降低，同时血红素加氧酶-1（一种炎症信号的负调节因子）被诱导。
我们的研究首次证明了瑞香素调节DCs功能以及随后Th细胞发育的特性。鉴于瑞香素的毒性较低或无毒性，我们的数据可能提示一种控制自身免疫性神经炎症的新型安全有效方法。
