Compound C induces the ramification of murine microglia in anAMPK-independent and small rhogtpase-dependent manner
Compound C induces the ramification of murine microglia in anAMPK-independent and small rhogtpase-dependent manner
复制标题
化合物 C 以 AMPK 独立和小 rhogtpase 依赖性方式诱导小鼠小胶质细胞的分化
DOI：
10.1016/j.neuroscience.2016.06.018
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发表时间：
2016
期刊：
影响因子：
3.3
通讯作者：
Wei Zhang
中科院分区：
文献类型：
--
作者：
Chao Huang;Xu Lu;Jili Wang;Lijuan Tong;Yong Ling;Bo Jiang;Rongrong Yang;Wei Zhang
小胶质细胞是中枢神经系统的关键免疫细胞。成年小胶质细胞在生理条件下处于分支状态，具有广泛的分支突起。在疾病刺激下，它们缩回它们的过程并被激活。诱导分枝是一种终止小胶质细胞过度活化的吸引策略。在这里，我们研究了化合物C（CC）对小胶质细胞形状的影响。结果表明，CC可逆地诱导衍生的小鼠小胶质细胞在基础和炎症条件。这些前衍生作用不依赖于腺苷5′-一磷酸活化蛋白激酶（AMPK）抑制，因为AMPKα1和AMPKα2沉默均不能诱导小胶质细胞衍生。CC诱导的小胶质细胞的分枝状态与促炎因子的减少和脑源性神经营养因子（BDNF）蛋白和吞噬活性的增加相关。机制研究证实，磷脂酰肌醇3-激酶（PI 3 K）-蛋白激酶B（Akt）信号、细胞外信号调节激酶1/2（ERK 1/2）或小RhoGT 3激活介导CC对小胶质细胞形状改变的作用，基于以下观察：（i）CC诱导小RhoGT 3 Rac 1和Cdc 42的显著激活;（ii）CC促进ERK 1/2和Akt的磷酸化;（iii）Rac 1、Cdc 42、ERK 1/2或PI 3 K-Akt信号的抑制消除了CC对小胶质细胞形状改变的影响。这些信号机制也在初级小胶质细胞中得到证实。我们的研究结果探索了一种促进小胶质细胞衍生的潜在药物，并为CC在各种疾病模型（如脑缺血和蛛网膜下腔出血）中的神经保护作用提供了另一种解释。
Microglial cells are the pivotal immune cells of the central nervous system. Adult microglia cells under physiological conditions are in a ramification state with extensively branched processes. Upon disease stimulation, they retract their processes and become activated. Induction of ramification is an attracting strategy to terminate the excessive activation of microglia. Here, we investigated the influence of compound C (CC) on microglial shape. Results showed that CC reversibly induced a ramification of murine microglia in both basal and inflammatory conditions. These pro-ramification effects were independent of adenosine 5′-monophosphate-activated protein kinase (AMPK) inhibition as both AMPKα1 and AMPKα2 silence failed to induce microglial ramification. The ramification state of microglia induced by CC was associated with a decrease in pro-inflammatory factors and an increase in brain-derived neurotrophic factors (BDNF) protein and phagocytic activity. Mechanistic studies confirmed that the phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt) signal, extracellular signal-regulated kinase 1/2 (ERK1/2) or small RhoGTPase activation mediated the effect of CC on microglial shape change based on the following observations: (i) CC induced a significant activation of the small RhoGTPase Rac1 and Cdc42; (ii) CC promoted the phosphorylation of ERK1/2 and Akt; (iii) inhibition of Rac1, Cdc42, ERK1/2, or the PI3K–Akt signal abolished the effect of CC on microglial shape change. These signal mechanisms were also ascertained in primary microglia. Our results explore a potential agent that promotes microglial ramification, and provide an alternative explanation for the neuroprotective effects of CC in various disease models such as brain ischemia and subarachnoid hemorrhage.