Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, 450052, China.
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, 450052, China.
Exp Cell Res. 2020 Apr 15;389(2):111912. doi: 10.1016/j.yexcr.2020.111912. Epub 2020 Feb 19.
Ischemic stroke leads to neuronal cell death and induces a cascade of inflammatory signals that results in secondary brain damage. Although constant efforts to develop therapeutic strategies and to reveal the molecular mechanism resulting in the physiopathology of this disease, much still remains unclear. Membrane-bound Toll-like receptors (TLRs) and cytosolic nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) are two major families of pattern recognition receptors that initiate pro-inflammatory signaling pathways. In the present study, we explored the role of NLRP10 in regulating inflammatory responses in acute ischemic stroke using the wild type (WT) and NLRP10 knockout (KO) mice by inducing middle cerebral artery occlusion/reperfusion (MCAO) injuries. The study first showed that NLRP10 was over-expressed in the ischemic penumbra of WT mice. Then, the brain infarct volume was significantly decreased, and the moving activity was improved post-MCAO in mice with NLRP10 knockout. Apoptosis was also alleviated by NLRP10-knockout, as evidenced by the decreased number of TUNEL-staining cells. Further, NLRP10 deficiency attenuated the activation of glia cells in hippocampus of mice with MCAO operation. NLRP10 inhibition ameliorated the levels of inflammatory factors in peripheral blood serum and hippocampus of mice after stroke. The activation of toll-like receptor (TLR)-4/nuclear factor-κB (NF-κB) signaling pathways was markedly suppressed by NLRP10 ablation in mice after MCAO treatment. Importantly, inflammasome, including NLRP12, ASC and Caspase-1, induced by MCAO in hippocampus of mice was clearly impeded by the loss of NLRP10. The results above were mainly verified in LPS-incubated astrocytes in the absence of NLRP10. Correspondingly, in LPS-treated astrocytes, NLRP10 knockout-reduced inflammation via impairing TLR-4/NF-κB and NLRP12/ASC/Caspase-1 pathways was evidently restored by over-expressing NLRP10. Therefore, the results above indicated an essential role of NLRP10 in regulating ischemic stroke, presenting NLRP10 as a promising target to protect human against stroke.
缺血性中风导致神经元细胞死亡，并诱导一系列炎症信号，导致继发性脑损伤。尽管不断努力开发治疗策略并揭示导致这种疾病病理生理学的分子机制，但仍有许多问题尚未阐明。膜结合 Toll 样受体 (TLR) 和细胞质核苷酸结合寡聚化结构域 (NOD)-样受体 (NLR) 是启动促炎信号通路的两种主要模式识别受体家族。在本研究中，我们使用野生型 (WT) 和 NLRP10 敲除 (KO) 小鼠通过诱导大脑中动脉闭塞/再灌注 (MCAO) 损伤，探讨了 NLRP10 在调节急性缺血性中风中的炎症反应中的作用。研究首先表明，NLRP10 在 WT 小鼠的缺血半影区过度表达。然后，NLRP10 敲除小鼠的脑梗死体积显著减小，MCAO 后运动活动改善。NLRP10 敲除也减轻了细胞凋亡，TUNEL 染色细胞数量减少。此外，NLRP10 缺乏可减轻 MCAO 手术小鼠海马中的神经胶质细胞激活。NLRP10 抑制可改善中风后小鼠外周血血清和海马中炎症因子的水平。NLRP10 缺失可显著抑制 MCAO 治疗后小鼠 TLR-4/核因子-κB (NF-κB) 信号通路的激活。重要的是，MCAO 诱导的小鼠海马中的炎性小体，包括 NLRP12、ASC 和 Caspase-1，在 NLRP10 缺失后明显受到抑制。上述结果主要在没有 NLRP10 的 LPS 孵育的星形胶质细胞中得到验证。相应地，在 LPS 处理的星形胶质细胞中，NLRP10 敲除通过损害 TLR-4/NF-κB 和 NLRP12/ASC/Caspase-1 通路减少炎症，而过表达 NLRP10 可明显恢复。因此，上述结果表明 NLRP10 在调节缺血性中风中起着重要作用，为保护人类免受中风提供了一个有前途的靶点。
