Dimethyl fumarate attenuates experimental autoimmune neuritis through the nuclear factor erythroid-derived 2-related factor 2/hemoxygenase-1 pathway by altering the balance of M1/M2 macrophages.
Dimethyl fumarate attenuates experimental autoimmune neuritis through the nuclear factor erythroid-derived 2-related factor 2/hemoxygenase-1 pathway by altering the balance of M1/M2 macrophages.
复制标题
富马酸二甲酯通过改变 M1/M2 巨噬细胞的平衡，通过核因子红细胞衍生 2 相关因子 2/hemoxygenase-1 途径减轻实验性自身免疫性神经炎。
DOI：
10.1186/s12974-016-0559-x
复制
发表时间：
2016-05-03
影响因子：
9.3
通讯作者：
Hao J
中科院分区：
文献类型：
--
作者：
Han R;Xiao J;Zhai H;Hao J
格林-巴利综合征 (GBS) 是一种急性、感染后、免疫介导的周围神经和神经根脱髓鞘疾病。富马酸二甲酯 (DMF) 是一种富马酸酯，具有多种生物活性，包括多种免疫调节和神经保护作用。然而，DMF 在 GBS 动物模型实验性自身免疫性神经炎 (EAN) 中作用的潜在机制尚不清楚。使用 EAN（一种已建立的 GBS 模型），我们通过评估临床评分、组织学染色和电生理学研究来研究 DMF 的作用。然后，我们通过蛋白质印迹分析、流式细胞术、荧光免疫组织化学、PCR和ELISA分析进一步探讨了潜在的机制。曼-惠特尼 U 检验用于在适当的情况下比较对照组和治疗组之间的差异。 DMF 治疗通过改善坐骨神经的炎症细胞浸润和脱髓鞘来减少神经功能缺损。此外，DMF治疗降低了EAN大鼠脾脏和坐骨神经中促炎M1巨噬细胞的水平，同时增加了抗炎M2巨噬细胞的数量。在 RAW 264.7 中，巨噬细胞极化从 M1 表型到 M2 表型的转变被证明取决于 DMF 的应用。在坐骨神经中，DMF 治疗提高了抗氧化转录因子核因子红细胞衍生 2 相关因子 2 (Nrf2) 及其靶基因 hemoxygenase-1 (HO-1) 的水平，这可以促进巨噬细胞向 M2 型极化。此外，DMF 改善了 EAN 大鼠脾脏的炎症环境，其特征是 IFN-γ、TNF-α、IL-6 和 IL-17 的信使 RNA (mRNA) 下调，以及 IL-4 和 IL-10 mRNA 水平上调。综上所述，我们的数据表明 DMF 可以有效抑制 EAN，其机制涉及改变 M1/M2 巨噬细胞的平衡并减轻炎症。本文的在线版本 (doi:10.1186/s12974-016-0559-x) 包含补充材料，可供授权用户使用。
Guillain–Barré syndrome (GBS) is an acute, post-infectious, immune-mediated, demyelinating disease of peripheral nerves and nerve roots. Dimethyl fumarate (DMF), a fumaric acid ester, exhibits various biological activities, including multiple immunomodulatory and neuroprotective effects. However, the potential mechanism underlying the effect of DMF in GBS animal model experimental autoimmune neuritis (EAN) is unclear. Using EAN, an established GBS model, we investigated the effect of DMF by assessing clinical score, histological staining and electrophysiological studies. Then, we further explored the potential mechanism by Western blot analysis, flow cytometry, fluorescence immunohistochemistry, PCR, and ELISA analysis. The Mann–Whitney U test was used to compare differences between control group and treatment groups where appropriate. DMF treatment reduced the neurological deficits by ameliorating inflammatory cell infiltration and demyelination of sciatic nerves. In addition, DMF treatment decreased the level of pro-inflammatory M1 macrophages while increasing the number of anti-inflammatory M2 macrophages in the spleens and sciatic nerves of EAN rats. In RAW 264.7, a shift in macrophage polarization from M1 to M2 phenotype was demonstrated to be depended on DMF application. In sciatic nerves, DMF treatment elevated the level of the antioxidant transcription factor nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and its target gene hemoxygenase-1 (HO-1) which could facilitate macrophage polarization toward M2 type. Moreover, DMF improved the inflammatory milieu in spleens of EAN rats, characterized by downregulation of messenger RNA (mRNA) of IFN-γ, TNF-α, IL-6, and IL-17 and upregulation of mRNA level of IL-4 and IL-10. Taken together, our data demonstrate that DMF can effectively suppress EAN, and the mechanism involves altering the balance of M1/M2 macrophages and attenuating inflammation. The online version of this article (doi:10.1186/s12974-016-0559-x) contains supplementary material, which is available to authorized users.