Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Sichuan Clinical Research Center for Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
Exp Neurol. 2022 Nov;357:114171. doi: 10.1016/j.expneurol.2022.114171. Epub 2022 Jul 21.
Targeting microglial activation has been shown to ameliorate early brain injury (EBI) after subarachnoid hemorrhage (SAH). Ferroptosis is a new form of programmed cell death after SAH, but these molecular features were not recognized as evidence of microglial function so far. In this study, we constructed microglial S100A8-specific knockdown and established the SAH model in vivo and in vitro. Multi-technology strategies, including high throughput sequencing, adeno-associated virus gene gene-editing and several molecular biotechnologies to validate the effects of S100A8 on microglial autophagy and ferroptosis after SAH. Our results revealed that the expression of S100A8 was significantly increased in brain tissue after SAH. Targeted microglial S100A8 inhibition improved neural function and neuronal apoptosis in mice after SAH. Further mechanism exploration found that favourable effects of S100A8 depletion in EBI may be through the inhibition of microglia autophagy-dependent ferroptosis. In conclusion, S100A8 may be a potential intervention target for microglial ferroptosis in EBI after SAH.
靶向小胶质细胞激活已被证明可改善蛛网膜下腔出血 (SAH) 后的早期脑损伤 (EBI)。铁死亡是 SAH 后一种新的程序性细胞死亡形式，但到目前为止，这些分子特征尚未被认为是小胶质细胞功能的证据。在这项研究中，我们构建了小胶质细胞 S100A8 特异性敲低，并在体内和体外建立了 SAH 模型。采用高通量测序、腺相关病毒基因编辑和几种分子生物技术等多技术策略，验证了 S100A8 对 SAH 后小胶质细胞自噬和铁死亡的影响。我们的结果表明，SAH 后脑组织中 S100A8 的表达明显增加。靶向小胶质细胞 S100A8 抑制可改善 SAH 后小鼠的神经功能和神经元凋亡。进一步的机制探索发现，S100A8 耗竭对 EBI 的有益作用可能是通过抑制小胶质细胞自噬依赖性铁死亡。总之，S100A8 可能是 SAH 后 EBI 中小胶质细胞铁死亡的潜在干预靶点。
