Lee Young-Sun, Gupta Deepak Prasad, Park Sung Hee, Yang Hyun-Jeong, Song Gyun Jee
Department of Medical Science, College of Medicine, Catholic Kwandong University, Gangneung, Korea.
Translational Brain Research Center, International St. Mary's Hospital, Catholic Kwandong University, Incheon, Korea.
Front Pharmacol. 2021 May 7;12:612981. doi: 10.3389/fphar.2021.612981. eCollection 2021.
Dimethyl fumarate (DMF), which has been approved by the Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis, is considered to exert anti-inflammatory and antioxidant effects. Microglia maintain homeostasis in the central nervous system and play a key role in neuroinflammation, while autophagy controls numerous fundamental biological processes, including pathogen removal, cytokine production, and clearance of toxic aggregates. However, the role of DMF in autophagy induction and the relationship of this effect with its anti-inflammatory functions in microglia are not well known. In the present study, we investigated whether DMF inhibited neuroinflammation and induced autophagy in microglia. First, we confirmed the anti-neuroinflammatory effect of DMF in mice with streptozotocin-induced diabetic neuropathy. Next, we used models including microglial cell lines and primary microglial cells to examine the anti-inflammatory and neuroprotective effects of DMF. We found that DMF significantly inhibited nitric oxide and proinflammatory cytokine production in lipopolysaccharide-stimulated microglia and induced the switch of microglia to the M2 state. In addition, DMF treatment increased the expression levels of autophagy markers including microtubule-associated protein light chain 3 (LC3) and autophagy-related protein 7 (ATG7) and the formation of LC3 puncta in microglia. The anti-inflammatory effect of DMF in microglia was significantly reduced by pretreatment with autophagy inhibitors. These data suggest that DMF leads to the induction of autophagy in microglia and that its anti-inflammatory effects are partially mediated through an autophagy-dependent pathway.
富马酸二甲酯（DMF）已获美国食品药品监督管理局批准用于治疗复发缓解型多发性硬化症，被认为具有抗炎和抗氧化作用。小胶质细胞维持中枢神经系统的稳态，并在神经炎症中起关键作用，而自噬控制着许多基本生物学过程，包括病原体清除、细胞因子产生和有毒聚集体的清除。然而，DMF在自噬诱导中的作用及其与小胶质细胞抗炎功能的关系尚不清楚。在本研究中，我们调查了DMF是否抑制小胶质细胞中的神经炎症并诱导自噬。首先，我们在链脲佐菌素诱导的糖尿病性神经病变小鼠中证实了DMF的抗神经炎症作用。接下来，我们使用包括小胶质细胞系和原代小胶质细胞在内的模型来研究DMF的抗炎和神经保护作用。我们发现，DMF显著抑制脂多糖刺激的小胶质细胞中一氧化氮和促炎细胞因子的产生，并诱导小胶质细胞向M2状态转变。此外，DMF处理增加了小胶质细胞中自噬标志物的表达水平，包括微管相关蛋白轻链3（LC3）和自噬相关蛋白7（ATG7），并促进了LC3斑点的形成。用自噬抑制剂预处理后，DMF在小胶质细胞中的抗炎作用显著降低。这些数据表明，DMF可诱导小胶质细胞自噬，其抗炎作用部分通过自噬依赖性途径介导。
