Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China.
State Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, People's Republic of China.
J Neurophysiol. 2021 Nov 1;126(5):1740-1750. doi: 10.1152/jn.00649.2020. Epub 2021 Oct 13.
We reported that a high level of autophagy was initiated by oxygen-glucose deprivation (OGD) and was maintained in neurons even after oxygen-glucose deprivation followed by reoxygenation (OGD/R), accompanied by neuronal apoptosis. This study focused on autophagy-induced apoptosis and its signaling network, especially the role of endoplasmic reticulum stress (ERS). Analysis of primary cultured cortical neurons from mice showed that the autophagy-induced apoptosis depended on caspase-8 and -9 but not on caspase-12. This finding did not mean that the endoplasmic reticulum did not participate in this process. Increases in the levels of endoplasmic reticulum (ER) biomarkers and binding immunoglobulin protein (BiP) were induced by autophagy in OGD/R-treated neurons. In addition, as an apoptotic transcription factor induced by ER stress, C/EBP homologous protein (CHOP) expression was significantly increased in neurons after OGD/R. This result suggested that the autophagy-BiP-CHOP-caspase (8 and 9)-dependent apoptotic signaling pathway at least partly participated in autophagy-induced apoptosis in primary cortical neurons. It revealed that ER induced apoptosis in neurons suffering from OGD/R injury in an ER stress-CHOP-dependent manner rather than a caspase-12-dependent manner. However, more research on signaling or cross-linking networks and intermediate links is needed. The realization of caspase-12-independent BiP-CHOP neuronal apoptosis pathway has expanded our understanding of the neuronal apoptosis network, which may eventually provide endogenous interventional strategies for OGD/R injury after stroke. ER stress induced by autophagy mediates caspase-8- and caspase-9-dependent apoptosis pathways by regulating CHOP in neurons exposed to OGD/R. We hypothesized that the autophagy-BiP-CHOP-caspase (8 and 9)-dependent apoptotic signaling pathway at least partly participated in autophagy-induced apoptosis in primary cortical neurons.
我们曾报道，在氧葡萄糖剥夺（OGD）后，自噬被引发且在氧葡萄糖再灌注（OGD/R）后仍能在神经元中维持，同时伴随着神经元凋亡。本研究聚焦于自噬诱导的凋亡及其信号网络，尤其是内质网应激（ERS）的作用。对来自小鼠的原代皮质神经元的分析表明，自噬诱导的凋亡依赖于半胱天冬酶-8 和 -9，但不依赖于半胱天冬酶-12。这一发现并不意味着内质网不参与这一过程。自噬在 OGD/R 处理的神经元中诱导内质网标志物和结合免疫球蛋白蛋白（BiP）水平升高。此外，作为内质网应激诱导的凋亡转录因子，C/EBP 同源蛋白（CHOP）在 OGD/R 后神经元中的表达明显增加。这一结果表明，自噬-BiP-CHOP-半胱天冬酶（8 和 9）依赖性凋亡信号通路至少部分参与了原代皮质神经元中的自噬诱导的凋亡。这表明 ER 通过 ER 应激-CHOP 依赖性而非 caspase-12 依赖性方式诱导 OGD/R 损伤神经元中的凋亡。然而，还需要更多关于信号或交联网络和中间环节的研究。 caspase-12 非依赖性 BiP-CHOP 神经元凋亡通路的实现扩展了我们对神经元凋亡网络的理解，这可能最终为中风后 OGD/R 损伤提供内源性干预策略。自噬诱导的 ER 应激通过调节 OGD/R 暴露的神经元中的 CHOP 介导 caspase-8 和 caspase-9 依赖性凋亡途径。我们假设，自噬-BiP-CHOP-半胱天冬酶（8 和 9）依赖性凋亡信号通路至少部分参与了原代皮质神经元中的自噬诱导的凋亡。
