Inhibition of mTOR pathway restrains astrocyte proliferation, migration and production of inflammatory mediators after oxygen-glucose deprivation and reoxygenation
Inhibition of mTOR pathway restrains astrocyte proliferation, migration and production of inflammatory mediators after oxygen-glucose deprivation and reoxygenation
复制标题
氧糖剥夺和复氧后，mTOR 通路的抑制可抑制星形胶质细胞的增殖、迁移和炎症介质的产生
DOI：
10.1016/j.neuint.2015.03.001
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发表时间：
2015-04-01
影响因子：
4.2
通讯作者：
Tian, Dai-Shi
中科院分区：
文献类型：
--
作者：
Li, Chun-Yu;Li, Xiao;Tian, Dai-Shi
神经胶质瘢痕是中枢神经系统疾病中轴突再生的主要障碍。克服这一物理和生化障碍可能是至关重要的轴突再生和功能补偿过程中的中枢神经系统疾病的进展。哺乳动物雷帕霉素靶蛋白（mTOR）是一种进化上保守的丝氨酸/苏氨酸激酶，参与细胞增殖、迁移、自噬和蛋白质合成等过程。雷帕霉素是mTOR信号传导的抑制剂，可以在几种CNS疾病中发挥神经保护作用。然而，它在脑缺血后反应性星形胶质细胞增生过程中的作用，包括细胞增殖、迁移和细胞因子的产生仍然是未知的。在这项研究中，我们研究了mTOR阻断在暴露于氧-葡萄糖剥夺/再给氧（OGD/R）的培养星形胶质细胞中的作用，OGD/R是一种广泛使用的细胞缺血模型，其模拟了理想的体内脑缺血模型。结果发现，OGD/R后星形胶质细胞活化，表现为星形胶质细胞形态改变，GFAP表达上调，Edu阳性细胞增多，并伴有mTOR蛋白及其底物S6 K1磷酸化。雷帕霉素可显著抑制mTOR信号通路，通过调节细胞周期进程抑制星形胶质细胞增殖。此外，雷帕霉素减弱了星形胶质细胞的迁移，并减轻了暴露于OGD/R的星形胶质细胞诱导的炎症因子如TNF-α和iNOS的产生。总之，我们的研究结果表明，雷帕霉素阻断mTOR减弱了星形胶质细胞的迁移，增殖和炎症介质的产生。我们认为，在星形胶质细胞活化中靶向mTOR通路可能代表了一种潜在的新的治疗策略，用于对抗中枢神经系统疾病（如缺血性卒中）中反应性星形胶质细胞增生的有害神经毒性过程。(C)2015爱思唯尔有限公司版权所有。
Glial scar is a major impediment to axonal regeneration in central nervous system (CNS) disorders. Overcoming this physical and biochemical barrier might be crucial for axonal regeneration and functional compensation during the progression of CNS disorders. The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase, involved in process of cell proliferation, migration, autophagy and protein synthesis. Rapamycin, an inhibitor of mTOR signaling, can exert neuroprotective effects in several CNS diseases. However, its role in the process of reactive astrogliosis including cell proliferation, migration and cytokine production after cerebral ischemia still remains largely unknown. In this study, we investigated the effects of mTOR blockade in cultured astrocytes exposed to oxygen-glucose deprivation/reoxygenation (OGD/R), a wildly used cellular ischemia model which mimics ideally cerebral ischemia model in vivo. We found that astrocytes became activated after OGD/R, characterized by change of astrocytic morphology, upregulation of GFAP expression, the increase number of Edu positive cells, and accompanied with phosphorylation of mTOR protein and its substrate S6K1. Rapamycin significantly inhibited mTOR signal pathway, suppressed proliferation of astrocytes via modulation of cell cycle progression. Moreover, rapamycin attenuated astrocytic migration and mitigated production of inflammatory factors such as TNF-alpha and iNOS induced by astrocytes exposed to OGD/R. Taken together, our findings indicated that mTOR blockade by rapamycin attenuates astrocyte migration, proliferation and production of inflammation mediators. We suggest that targeting mTOR pathway in astrocyte activation may represent a potentially new therapeutic strategy against deleterious neurotoxic processes of reactive astrogliosis in CNS disorders such as ischemic stroke. (C) 2015 Elsevier Ltd. All rights reserved.