Microglial Pro-Inflammatory and Anti-Inflammatory Phenotypes Are Modulated by Translocator Protein Activation
Microglial Pro-Inflammatory and Anti-Inflammatory Phenotypes Are Modulated by Translocator Protein Activation
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DOI：
10.3390/ijms20184467
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发表时间：
2019-09-02
影响因子：
5.6
通讯作者：
Martini, Claudia
中科院分区：
文献类型：
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作者：
Da Pozzo, Eleonora;Tremolanti, Chiara;Martini, Claudia
线粒体转运蛋白18kda （TSPO）在神经炎症中的关键作用最近被提出。然而，人们对tspo激活的反应性小胶质细胞调节通路知之甚少。本研究在体外人原代小胶质细胞模型（永生化C20细胞）中探讨了炎症刺激下TSPO的激活。使用了两种不同的方法，目的是(i)从药理学上放大或（ii）通过慢病毒短发夹RNA沉默TSPO的生理功能。在TSPO药理刺激模型中，合成的类固醇选择性配体XBD-173可减弱小胶质细胞的活化。事实上，它分别减少和增加促炎和抗炎细胞因子的释放。当甾体生成抑制剂氨基乙硫胺处理C20细胞时，这种配体诱导的效应被消除。这表明神经类固醇在调节白细胞介素产生中的作用。高甾体性配体XBD-173比低甾体性配体更有效地减轻神经炎症反应，这表明观察到的对细胞因子释放的调节可能受到产生的神经甾体水平的影响。在TSPO沉默模型中，TSPO的减少导致了混乱细胞的炎症表型。同样，在炎症反应中，TSPO沉默分别增加和减少促炎和抗炎细胞因子的释放。综上所述，本研究结果支持TSPO在人小胶质细胞介导的炎症反应中，在抗炎和促炎介质之间的动态平衡中起稳态作用。有趣的是，我们的初步结果表明，在炎症反应的激活过程中，NF-kappa B可以刺激TSPO的表达。
A key role of the mitochondrial Translocator Protein 18 KDa (TSPO) in neuroinflammation has been recently proposed. However, little is known about TSPO-activated pathways underlying the modulation of reactive microglia. In the present work, the TSPO activation was explored in an in vitro human primary microglia model (immortalized C20 cells) under inflammatory stimulus. Two different approaches were used with the aim to (i) pharmacologically amplify or (ii) silence, by the lentiviral short hairpin RNA, the TSPO physiological function. In the TSPO pharmacological stimulation model, the synthetic steroidogenic selective ligand XBD-173 attenuated the activation of microglia. Indeed, it reduces and increases the release of pro-inflammatory and anti-inflammatory cytokines, respectively. Such ligand-induced effects were abolished when C20 cells were treated with the steroidogenesis inhibitor aminoglutethimide. This suggests a role for neurosteroids in modulating the interleukin production. The highly steroidogenic ligand XBD-173 attenuated the neuroinflammatory response more effectively than the poorly steroidogenic ones, which suggests that the observed modulation on the cytokine release may be influenced by the levels of produced neurosteroids. In the TSPO silencing model, the reduction of TSPO caused a more inflamed phenotype with respect to scrambled cells. Similarly, during the inflammatory response, the TSPO silencing increased and reduced the release of pro-inflammatory and anti-inflammatory cytokines, respectively. In conclusion, the obtained results are in favor of a homeostatic role for TSPO in the context of dynamic balance between anti-inflammatory and pro-inflammatory mediators in the human microglia-mediated inflammatory response. Interestingly, our preliminary results propose that the TSPO expression could be stimulated by NF-kappa B during activation of the inflammatory response.