Astrocytes Surviving Severe Stress Can Still Protect Neighboring Neurons from Proteotoxic Injury.
Astrocytes Surviving Severe Stress Can Still Protect Neighboring Neurons from Proteotoxic Injury.
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DOI：
10.1007/s12035-015-9427-4
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发表时间：
2016-09
影响因子：
5.1
通讯作者：
Leak RK
中科院分区：
文献类型：
--
作者：
Gleixner AM;Posimo JM;Pant DB;Henderson MP;Leak RK
星形胶质细胞是对抗细胞应激和保护邻近神经元免受损伤的主要细胞类型之一。为了履行这一重要作用，星形胶质细胞必须感知并响应有毒刺激，可能包括严重应激并杀死一些星形胶质细胞的刺激。本研究表明，能够在严重的蛋白毒性应激下存活下来的初级星形胶质细胞受到保护，免受随后的挑战。这些发现表明，对于这种细胞类型，预处理或耐受现象可以从轻度应激扩展到重度应激。星形胶质细胞的应激适应持续至少 96 小时，这是测试的最长间隔。热休克蛋白 70 (Hsp70) 在应激星形胶质细胞中升高，但抑制 Hsp70 和 Hsp32 活性都不能消除它们对第二次蛋白毒性攻击的抵抗力。只有抑制谷胱甘肽合成才能消除星形胶质细胞的应激适应，这与我们之前的报告一致。将原代神经元铺在先前受到应激的星形胶质细胞上，然后将共培养物暴露于另一种蛋白毒性挑战。受到严重压力的星形胶质细胞仍然能够保护邻近的神经元免受这种损伤，并且这种保护出乎意料地独立于谷胱甘肽的合成。在同时使用蛋白酶体和 Hsp70 抑制剂后，应激的星形胶质细胞甚至能够保护神经元，否则当同时使用时，会引起协同的、严重的神经元损失。星形胶质细胞条件培养基并未引发星形胶质细胞诱导的针对蛋白毒性的神经保护作用，这表明细胞间的物理接触可能是必要的。这些发现表明星形胶质细胞可能适应严重的压力，以便它们能够继续保护邻近的细胞类型免受严重损伤。
Astrocytes are one of the major cell types to combat cellular stress and protect neighboring neurons from injury. In order to fulfill this important role, astrocytes must sense and respond to toxic stimuli, perhaps including stimuli that are severely stressful and kill some of the astrocytes. The present study demonstrates that primary astrocytes that managed to survive severe proteotoxic stress were protected against subsequent challenges. These findings suggest that the phenomenon of preconditioning or tolerance can be extended from mild to severe stress for this cell type. Astrocytic stress adaptation lasted at least 96 hours, the longest interval tested. Heat shock protein 70 (Hsp70) was raised in stressed astrocytes, but inhibition of neither Hsp70 nor Hsp32 activity abolished their resistance against a second proteotoxic challenge. Only inhibition of glutathione synthesis abolished astrocytic stress adaptation, consistent with our previous report. Primary neurons were plated upon previously stressed astrocytes and the co-cultures were then exposed to another proteotoxic challenge. Severely stressed astrocytes were still able to protect neighboring neurons against this injury and the protection was unexpectedly independent of glutathione synthesis. Stressed astrocytes were even able to protect neurons after simultaneous application of proteasome and Hsp70 inhibitors, which otherwise elicited synergistic, severe loss of neurons when applied together. Astrocyte-induced neuroprotection against proteotoxicity was not elicited with astrocyte-conditioned media, suggesting that physical cell-to-cell contacts may be essential. These findings suggest that astrocytes may adapt to severe stress so that they can continue to protect neighboring cell types from profound injury.