Irisin protects against neuronal injury induced by oxygen-glucose deprivation in part depends on the inhibition of ROS-NLRP3 inflammatory signaling pathway
Irisin protects against neuronal injury induced by oxygen-glucose deprivation in part depends on the inhibition of ROS-NLRP3 inflammatory signaling pathway
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DOI：
10.1016/j.molimm.2017.09.014
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发表时间：
2017-11-01
影响因子：
3.6
通讯作者：
Xu, Fang-yuan
中科院分区：
文献类型：
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作者：
Peng, Juan;Deng, Xian;Xu, Fang-yuan
最近的研究发现，在运动中新发现的一种骨骼肌源性肌动蛋白，也在不同种类的组织中合成，对脑缺血时的神经元损伤具有保护作用。NLRP3炎性小体在检测细胞损伤和介导无菌组织损伤的炎症反应中发挥重要作用。然而，目前还不清楚淫羊藿素是否参与了缺血性卒中时NLRP3炎性小体激活的调节。在本研究中，PC12神经细胞暴露于缺氧缺糖环境中，外源性淫羊藿苷(12.5，25，50nmol/L)或NLRP3抑制剂格列本脲(50,100,200mU/L)作为干预剂，NLRP3表达载体或NLRP3特异性siRNA分别过表达或抑制NLRP3的表达。我们的数据显示，淫羊藿素及其前体蛋白纤维连接蛋白III型结构域5(FNDC5)的表达显著下调(p<；0.05)，但氧化应激和ROS-NLRP3炎症信号被OGD激活(p<；0.05)；用淫羊藿素处理或抑制NLRP3可逆转OGD诱导的氧化应激和炎症(p<；0.05)。然而，过度表达NLRP3使这些由淫羊藿素介导的作用减弱(p<；0.05)。综上所述，我们的结果首次揭示了淫羊藿素部分通过抑制ROS-NLRP3炎症信号通路减轻OGD诱导的神经元损伤，提示了淫羊藿素治疗缺血性卒中的可能机制。
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, 50 nmol/L) or NLRP3 inhibitor glyburide (50, 100, 200 mu mol/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.