Dai Qingqing, Han Song, Liu Ting, Zheng Jiayin, Liu Cui, Li Junfa, Li Shujuan
Department of Neurology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
Department of Neurobiology and Center of Stroke, Beijing Institute for Brain Disorders, School of Basic Medical Science, Capital Medical University, Beijing, China.
Front Aging Neurosci. 2020 Sep 4;12:274. doi: 10.3389/fnagi.2020.00274. eCollection 2020.
We previously reported that the levels of astrocyte-derived interleukin-17A (IL-17A) increased both in the peri-infarct region and cerebrospinal fluid (CSF) of mice with 1-h middle cerebral artery (MCA) occlusion/12-h reperfusion (1-h MCAO/R 12 h)-induced ischemic stroke. However, the effects of IL-17A neutralization on the neurological outcome of mice with ischemic stroke and its underlying molecular mechanism are unclear. In this study, we found that the intracerebroventricular injection of IL-17A-neutralizing monoclonal antibody (mAb; 2.0 μg) could reduce the infarct volume, alleviate neuron loss, and improve the neurological outcomes of mice with 1-h MCAO/R 24-h- or 3-day-induced ischemic-stroke mice. The IL-17A neutralization could also significantly inhibit the increase of pro-caspase-3 cleavage through caspase-12-dependent cell apoptosis, as well as preventing the decrease of antiapoptotic factor B-cell lymphoma 2 (Bcl-2) and the increase of proapoptotic Bcl-2-associated X protein (Bax) in the peri-infarct region of mice following ischemic stroke. In addition, we confirmed that the recombinant mouse (rm) IL-17A could significantly aggravate 1-h oxygen-glucose deprivation/24-h reoxygenation (1-h OGD/R 24 h)-induced ischemic injuries in cortical neurons in a dose-dependent manner, and the rmIL-17A could also exacerbate neuronal apoptosis through caspase-12 (not caspase-8 or caspase-9)-dependent pathway. These results suggest that IL-17A neutralization could improve the neurological outcome of mice with ischemic stroke through inhibiting caspase-12-dependent neuronal apoptosis.
我们之前报道过，在大脑中动脉闭塞1小时/再灌注12小时（1-h MCAO/R 12 h）诱导的缺血性脑卒中小鼠的梗死周围区域和脑脊液（CSF）中，星形胶质细胞衍生的白细胞介素-17A（IL-17A）水平均升高。然而，IL-17A中和对缺血性脑卒中小鼠神经功能结局的影响及其潜在分子机制尚不清楚。在本研究中，我们发现脑室内注射IL-17A中和单克隆抗体（mAb；2.0 μg）可减少梗死体积，减轻神经元丢失，并改善1-h MCAO/R 24小时或3天诱导的缺血性脑卒中小鼠的神经功能结局。IL-17A中和还可通过半胱天冬酶-12依赖性细胞凋亡显著抑制前半胱天冬酶-3的切割增加，并防止缺血性脑卒中后小鼠梗死周围区域抗凋亡因子B细胞淋巴瘤2（Bcl-2）的减少和促凋亡的Bcl-2相关X蛋白（Bax）的增加。此外，我们证实重组小鼠（rm）IL-17A可显著加重1小时氧糖剥夺/24小时复氧（1-h OGD/R 24 h）诱导的皮质神经元缺血性损伤，且呈剂量依赖性，rmIL-17A还可通过半胱天冬酶-12（而非半胱天冬酶-8或半胱天冬酶-9）依赖性途径加剧神经元凋亡。这些结果表明，IL-17A中和可通过抑制半胱天冬酶-12依赖性神经元凋亡改善缺血性脑卒中小鼠的神经功能结局。
