Abstract：
Interleukin-17 A (IL-17 A) contributes to inflammation and causes secondary injury in post-stroke patients. However, little is known regarding the mechanisms that IL-17 A is implicated in the processes of neuronal death during ischemia. In this study, the mouse models of middle cerebral artery occlusion/reperfusion (MCAO/R)-induced ischemic stroke and oxygen-glucose deprivation/reoxygenation (OGD/R)-simulated in vitro ischemia in neurons were employed to explore the role of IL-17 A in promoting neuronal apoptosis. Mechanistically, endoplasmic reticulum stress (ERS)-induced neuronal apoptosis was accelerated by IL-17 A activation through the caspase-12-dependent pathway. Blocking calpain or phospholipase Cγ (PLCγ) inhibited IL-17 A-mediated neuronal apoptosis under ERS by inhibiting caspase-12 cleavage. Src and IL-17 A are linked, and PLCγ directly binds to activated Src. This binding causes intracellular Ca2+ flux and activates the calpain-caspase-12 cascade in neurons. The neurological scores showed that intracerebroventricular (ICV) injection of an IL-17 A neutralizing mAb decreased the severity of I/R-induced brain injury and suppressed apoptosis in MCAO mice. Our findings reveal that IL-17 A increases caspase-12-mediated neuronal apoptosis, and IL-17 A suppression may have therapeutic potential for ischemic stroke.
摘要：
白细胞介素-17A（IL-17A）有助于中风后患者的炎症并引起继发性损伤。然而,关于IL-17A参与缺血期间神经元死亡过程的机制知之甚少。在这项研究中,采用小鼠大脑中动脉阻塞/再灌注（MCAO/R）诱导的缺血性卒中模型和体外模拟的神经元缺氧葡萄糖剥夺/复氧（OGD/R）模型，以探讨IL-17A在促进神经元凋亡中的作用。机械上,内质网应激（ERS）诱导的神经元凋亡通过caspase-12依赖性途径激活IL-17A而加速。阻断钙蛋白酶或磷脂酶Cγ（PLCγ）通过抑制caspase-12裂解来抑制ERS下IL-17A介导的神经元凋亡。Src和IL-17A是相连的,和PLCγ直接与活化的Src结合。这种结合引起细胞内Ca2+流动并激活神经元中的calpain-caspase-12级联。神经学评分显示脑室内(ICV)注射IL-17A中和mAb降低了I/R诱导的脑损伤的严重程度并抑制了MCAO小鼠的细胞凋亡。我们的发现表明，IL-17A增加caspase-12介导的神经元凋亡，和IL-17A抑制可能对缺血性卒中具有治疗潜力。
