Liu Lu, Chen Manli, Lin Kun, Xiang Xuwu, Zheng Yueying, Zhu Shengmei
Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People's Republic of China.
Int J Med Sci. 2020 Jul 19;17(13):1936-1945. doi: 10.7150/ijms.44330. eCollection 2020.
Stroke is one of the leading causes of death worldwide. Accumulating evidence suggests that NLRP3 inflammasome activation plays an important role in ischemic stroke injury. However, the existence of the NLRP3 inflammasome in astrocytes remains controversial. In this study, we demonstrated the presence of the NLRP3 inflammasome in primary mouse astrocytes and investigated the role of caspase-12 in NLRP3 inflammasome activation and cell injury in an astrocyte oxygen-glucose deprivation (OGD) model. Astrocytes exposed to 2, 3, and 4 h of OGD exhibited increased cell injury and apoptosis, and the protein levels of caspase-12, cleaved caspase-3, NLRP3 inflammasome components, and IL-1β were also significantly elevated. Interestingly, pretreatment with the caspase-12-specific inhibitor Z-ATAD-FMK attenuated cell injury and apoptosis and decreased the levels of NLRP3, caspase-1, IL-1β, and cleaved caspase-3 in the OGD group. In conclusion, Z-ATAD-FMK protected astrocytes against OGD-induced cell death and inhibited NLPR3-inflammasome activation. Our results indicate that caspase-12 and its potential regulation of NLRP3 inflammasome activation might be a promising target for treatment of ischemic stroke.
中风是全球主要死因之一。越来越多的证据表明，NLRP3炎性小体激活在缺血性中风损伤中起重要作用。然而，星形胶质细胞中NLRP3炎性小体的存在仍存在争议。在本研究中，我们证实了原代小鼠星形胶质细胞中存在NLRP3炎性小体，并在星形胶质细胞氧糖剥夺（OGD）模型中研究了半胱天冬酶-12在NLRP3炎性小体激活和细胞损伤中的作用。暴露于2、3和4小时OGD的星形胶质细胞表现出细胞损伤和凋亡增加，半胱天冬酶-12、裂解的半胱天冬酶-3、NLRP3炎性小体成分和白细胞介素-1β的蛋白水平也显著升高。有趣的是，用半胱天冬酶-12特异性抑制剂Z-ATAD-FMK预处理可减轻细胞损伤和凋亡，并降低OGD组中NLRP3、半胱天冬酶-1、白细胞介素-1β和裂解的半胱天冬酶-3的水平。总之，Z-ATAD-FMK保护星形胶质细胞免受OGD诱导的细胞死亡，并抑制NLPR3炎性小体激活。我们的结果表明，半胱天冬酶-12及其对NLRP3炎性小体激活的潜在调节可能是治疗缺血性中风的一个有前景的靶点。
