TSPO配体对小鼠小胶质细胞线粒体功能的差异影响,Psychoneuroendocrinology

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TSPO配体对小鼠小胶质细胞线粒体功能的差异影响
Psychoneuroendocrinology ( IF 3.4 ) Pub Date : 2019-08-01 , DOI: 10.1016/j.psyneuen.2019.03.029
Stefanie Bader ₁ , Luisa Wolf ₁ , Vladimir M Milenkovic ₁ , Michael Gruber ₂ , Caroline Nothdurfter ₁ , Rainer Rupprecht ₁ , Christian H Wetzel ₁

Affiliation

转运蛋白 18 kDa (TSPO)，最初表征为外周苯二氮卓受体，是一种保守的线粒体外膜蛋白，参与胆固醇转运，从而影响类固醇激素的生物合成，以及与生物能量学、氧化应激和 Ca2+ 相关的一般线粒体功能体内平衡。TSPO在类固醇生成组织如肾上腺中高度表达，但在中枢神经系统中表达低。在炎症、神经变性或癌症等各种疾病状态下，受累组织中线粒体 TSPO 的表达上调。TSPO 的表达可以通过高亲和力放射性配体进行追踪以用于诊断目的。此外，TSPO 的功能受到具有激动或拮抗特性的合成配体和内源性配体的调节。因此，TSPO 配体作为重要的生物标志物和推定的治疗剂发挥作用。在本研究中，我们旨在表征 TSPO 配体对表达显着水平 TSPO 的小鼠 BV-2 小胶质细胞的影响，并分析了 XBD173、PK11195 和 Ro5-4864 以及炎症试剂脂多糖的影响(LPS) 对神经类固醇合成和基本线粒体功能，如氧化磷酸化、线粒体膜电位和 Ca2+ 稳态。通过将慢病毒 TSPO 敲低与 shRNA 乱序对照和野生型 BV-2 细胞进行比较，将特定的 TSPO 依赖性效应与脱靶效应分开。我们的数据以 TSPO 依赖性或独立的方式证明了配体特异性对不同细胞功能的影响，为特定 TSPO 介导的、

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Differential effects of TSPO ligands on mitochondrial function in mouse microglia cells

The translocator protein 18 kDa (TSPO), initially characterized as peripheral benzodiazepine receptor, is a conserved outer mitochondrial membrane protein, implicated in cholesterol transport thereby affecting steroid hormone biosynthesis, as well as in general mitochondrial function related to bioenergetics, oxidative stress, and Ca2+ homeostasis. TSPO is highly expressed in steroidogenic tissues such as adrenal glands, but shows low expression in the central nervous system. During various disease states such as inflammation, neurodegeneration or cancer, the expression of mitochondrial TSPO in affected tissues is upregulated. The expression of TSPO can be traced for diagnostic purpose by high affinity radio-ligands. Moreover, the function of TSPO is modulated by synthetic as well as endogenous ligands with agonistic or antagonistic properties. Thus, TSPO ligands serve functions as both important biomarkers and putative therapeutic agents. In the present study, we aimed to characterize the effects of TSPO ligands on mouse BV-2 microglia cells, which express significant levels of TSPO, and analyzed the effect of XBD173, PK11195, and Ro5-4864, as well as the inflammatory reagent Lipopolysaccharides (LPS) on neurosteroid synthesis and on basic mitochondrial functions such as oxidative phosphorylation, mitochondrial membrane potential and Ca2+ homeostasis. Specific TSPO-dependent effects were separated from off-target effects by comparing lentiviral TSPO knockdown with shRNA scramble-controls and wild-type BV-2 cells. Our data demonstrate ligand-specific effects on different cellular functions in a TSPO-dependent or independent manner, providing evidence for both specific TSPO-mediated, as well as off-target effects.

更新日期：2019-08-01

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