Peng Juan, Deng Xian, Huang Wei, Yu Ji-Hua, Wang Jian-Xiong, Wang Jie-Ping, Yang Shi-Bin, Liu Xi, Wang Li, Zhang Yun, Zhou Xiang-Yu, Yang Hui, He Yan-Zheng, Xu Fang-Yuan
Department of Rehabilitation, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, PR China.
Department of Vascular and Thyroid Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, P.R. China; Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, PR China; State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology), Avenida Wai Long, Taipa, Macau, PR China.
Mol Immunol. 2017 Nov;91:185-194. doi: 10.1016/j.molimm.2017.09.014. Epub 2017 Sep 30.
Recent studies found that irisin, a newly discovered skeletal muscle-derived myokine during exercise, is also synthesized in various tissues of different species and protects against neuronal injury in cerebral ischemia. The NOD-like receptor pyrin 3 (NLRP3) inflammasome play an important role in detecting cellular damage and mediating inflammatory responses to aseptic tissue injury during ischemic stroke. However, it is unclear whether irisin is involved in the regulation of NLRP3 inflammasome activation during ischemic stroke. In the present study, PC12 neuronal cells were exposed to oxygen-glucose deprivation (OGD), exogenous irisin (12.5, 25, 50nmol/L) or NLRP3 inhibitor glyburide (50, 100, 200μmol/L) were used as an intervention reagent, NLRP3 was over-expressed or suppressed by transfection with a NLRP3 expressing vector or NLRP3-specifc siRNA, respectively. Our data showed that both irisin and its precursor protein fibronectin type III domain containing 5 (FNDC5) expression were significantly down-regulated (p<0.05); but oxidative stress and ROS-NLRP3 inflammasome signaling were activated by OGD (p<0.05); treatment with irisin or inhibition of NLRP3 reversed OGD-induced oxidative stress and inflammation (p<0.05). However, these irisin-mediated effects were blunted by over-expression NLRP3 (p<0.05). Taken together, our results firstly revealed that irisin mitigated OGD-induced neuronal injury in part via inhibiting ROS-NLRP3 inflammatory signaling pathway, suggesting a likely mechanism for irisin-induced therapeutic effect in ischemic stroke.
最近的研究发现，鸢尾素是运动期间新发现的一种骨骼肌衍生的肌动蛋白，它也在不同物种的各种组织中合成，并能保护大脑缺血中的神经元损伤。NOD样受体吡啉3（NLRP3）炎性小体在检测细胞损伤和介导缺血性中风期间对无菌组织损伤的炎症反应中起重要作用。然而，尚不清楚鸢尾素是否参与缺血性中风期间NLRP3炎性小体激活的调节。在本研究中，将PC12神经元细胞暴露于氧葡萄糖剥夺（OGD），使用外源性鸢尾素（12.5、25、50nmol/L）或NLRP3抑制剂格列本脲（50、100、200μmol/L）作为干预试剂，分别用NLRP3表达载体或NLRP3特异性siRNA转染来过表达或抑制NLRP3。我们的数据显示，鸢尾素及其前体蛋白含III型纤连蛋白结构域5（FNDC5）的表达均显著下调（p<0.05）；但OGD激活了氧化应激和ROS-NLRP3炎性小体信号（p<0.05）；用鸢尾素处理或抑制NLRP3可逆转OGD诱导的氧化应激和炎症（p<0.05）。然而，这些鸢尾素介导的作用被NLRP3的过表达减弱（p<0.05）。综上所述，我们的结果首次揭示，鸢尾素部分通过抑制ROS-NLRP3炎症信号通路减轻OGD诱导的神经元损伤，提示鸢尾素在缺血性中风中诱导治疗作用的可能机制。
