Department of Neurosurgery, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, P R China.
Department of Neurosurgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, P R China.
Cell Death Dis. 2020 Jan 30;11(1):76. doi: 10.1038/s41419-020-2248-z.
Only a few types of inflammasomes have been described in central nervous system cells. Among these, the absent in melanoma 2 (AIM2) inflammasome is primarily found in neurons, is highly specific and can be activated only by double-stranded DNA. Although it has been demonstrated that the AIM2 inflammasome is activated by poly(deoxyadenylic-deoxythymidylic) acid sodium salt and leads to pyroptotic neuronal cell death, the role of AIM2 inflammasome-mediated pyroptosis in early brain injury (EBI) after subarachnoid haemorrhage (SAH) has rarely been studied. Thus, we designed this study to explore the mechanism of gasdermin D(GSDMD)-induced pyroptosis mediated by the AIM2 inflammasome in EBI after SAH. The level of AIM2 from the cerebrospinal fluid (CSF) of patients with SAH was detected. The pathway of AIM2 inflammasome-mediated pyroptosis, the AIM2/Caspase-1/GSDMD pathway, was explored after experimental SAH in vivo and in primary cortical neurons stimulated by oxyhaemoglobin (oxyHb) in vitro. Then, we evaluated GSDMD-induced pyroptosis mediated by the AIM2 inflammasome in AIM2 and caspase-1- deficient mice and primary cortical neurons generated through lentivirus (LV) knockdown. Compared with that of the control samples, the AIM2 level in the CSF of the patients with SAH was significantly increased. Pyroptosis-associated proteins mediated by the AIM2 inflammasome were significantly increased in vivo and in vitro following experimentally induced SAH. After AIM2 and caspase-1 were knocked down by an LV, GSDMD-induced pyroptosis mediated by the AIM2 inflammasome was alleviated in EBI after SAH. Intriguingly, when caspase-1 was knocked down, apoptosis was significantly suppressed via impeding the activation of caspase-3. GSDMD-induced pyroptosis mediated by the AIM2 inflammasome may be involved in EBI following SAH. The inhibition of AIM2 inflammasome activation caused by knocking down AIM2 and caspase-1 alleviates GSDMD-induced pyroptosis in EBI after SAH.
仅有少数几种炎性小体在中枢神经系统细胞中被描述。其中，缺失黑色素瘤 2（AIM2）炎性小体主要存在于神经元中，具有高度特异性，只能被双链 DNA 激活。虽然已经证明 AIM2 炎性小体被聚（脱氧腺苷酸-脱氧胸苷酸）钠盐激活，并导致神经元细胞发生细胞焦亡性死亡，但 AIM2 炎性小体介导的细胞焦亡在蛛网膜下腔出血（SAH）后早期脑损伤（EBI）中的作用很少被研究。因此，我们设计了这项研究，以探讨 SAH 后 AIM2 炎性小体介导的 gasdermin D（GSDMD）诱导的细胞焦亡的机制。检测了 SAH 患者脑脊液（CSF）中的 AIM2 水平。在体内实验性 SAH 及体外原代皮质神经元氧合血红蛋白（oxyHb）刺激后，探讨了 AIM2 炎性小体介导的细胞焦亡途径，即 AIM2/Caspase-1/GSDMD 途径。然后，我们在 AIM2 和 caspase-1 缺陷小鼠及通过慢病毒（LV）敲低产生的原代皮质神经元中评估了 AIM2 炎性小体介导的 GSDMD 诱导的细胞焦亡。与对照组相比，SAH 患者 CSF 中的 AIM2 水平明显升高。在体内和体外实验性 SAH 后，AIM2 炎性小体介导的与细胞焦亡相关的蛋白明显增加。通过 LV 敲低 AIM2 和 caspase-1 后，SAH 后 EBI 中由 AIM2 炎性小体介导的 GSDMD 诱导的细胞焦亡得到缓解。有趣的是，当敲低 caspase-1 时，通过抑制 caspase-3 的激活，凋亡明显受到抑制。AIM2 炎性小体介导的 GSDMD 诱导的细胞焦亡可能参与了 SAH 后的 EBI。通过敲低 AIM2 和 caspase-1 抑制 AIM2 炎性小体的激活，减轻了 SAH 后 EBI 中 GSDMD 诱导的细胞焦亡。
