Ding Mingxiang, Jin Lei, Wei Boyang, Cheng Wenping, Liu Wenchao, Li Xifeng, Duan Chuanzhi
Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou; Department of Cerebrovascular Intervention, Zhongshan City People's Hospital, Zhongshan, Guangdong Province, China.
Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
Neural Regen Res. 2024 May;19(5):1064-1071. doi: 10.4103/1673-5374.385311.
Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment. Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage. Previous studies have confirmed that tumor necrosis factor-stimulated gene-6 (TSG-6) can exert a neuroprotective effect by suppressing oxidative stress and apoptosis. However, no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid hemorrhage. In this study, a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation method. Our results indicated that TSG-6 expression was predominantly detected in astrocytes, along with NLRC4 and gasdermin-D (GSDMD). The expression of NLRC4, GSDMD and its N-terminal domain (GSDMD-N), and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological impairment. To explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage, recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral ventricles. Exogenous TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological deficits. Moreover, TSG-6 knockdown further increased the expression of NLRC4, which was accompanied by more severe astrocyte pyroptosis. In summary, our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis.
蛛网膜下腔出血与高发病率和死亡率相关，且缺乏有效的治疗方法。细胞焦亡是蛛网膜下腔出血后早期脑损伤的关键机制。先前的研究证实，肿瘤坏死因子刺激基因-6（TSG-6）可通过抑制氧化应激和细胞凋亡发挥神经保护作用。然而，迄今为止尚无研究探讨TSG-6是否能减轻蛛网膜下腔出血后早期脑损伤中的细胞焦亡。在本研究中，采用血管内穿刺法建立了C57BL/6J小鼠蛛网膜下腔出血模型。我们的结果表明，TSG-6主要在星形胶质细胞中表达，同时还有NLR家族CARD结构域蛋白4（NLRC4）和gasdermin-D（GSDMD）。蛛网膜下腔出血后，NLRC4、GSDMD及其N端结构域（GSDMD-N）以及裂解的半胱天冬酶-1的表达显著增强，并伴有脑水肿和神经功能障碍。为了探讨TSG-6如何影响蛛网膜下腔出血后早期脑损伤期间的细胞焦亡，将重组人TSG-6或靶向TSG-6的小干扰RNA（siRNA）注入脑室。外源性给予TSG-6可下调NLRC4和细胞焦亡相关蛋白的表达，并减轻脑水肿和神经功能缺损。此外，敲低TSG-6可进一步增加NLRC4的表达，并伴有更严重的星形胶质细胞焦亡。总之，我们的研究表明，TSG-6通过抑制NLRC4炎性小体激活诱导的星形胶质细胞焦亡，为蛛网膜下腔出血后的早期脑损伤提供神经保护。
