Department of Neurology, The First Affiliated Hospital of Xi'an Medical University, Xi'an, 710077, China.
Otolaryngology Department, The First Affiliated Hospital of Xi'an Medical University, Xi'an, 710077, China.
Biomed Pharmacother. 2019 Jul;115:108816. doi: 10.1016/j.biopha.2019.108816. Epub 2019 May 13.
Inflammation and immune responses are crucial factors associated with the onset and progression of stroke. Interleukin-11 (IL-11) is a hematopoietic IL-6 family cytokine that functions as an anti-inflammatory agent against various inflammatory diseases. However, its roles in stroke remain unknown. In this study, we investigated the effects of IL-11 on cerebral ischemia-reperfusion injury in a model of focal cerebral ischemia.
Mice were randomly divided into five groups the vehicle group, the middle cerebral artery occlusion (MCAO) group, the MCAO plus adenosine monophosphate-activated protein kinase (AMPK) inhibitor compound C group, the MCAO plus IL-11 treatment group, and the MCAO plus IL-11 treatment and compound C group. Focal cerebral ischemia was induced by occluding the left middle cerebral artery, and reperfusion was achieved by withdrawing the suture 2 h after ischemia. The protein expression levels of IL-11 were measured using Western blot analysis, and its location was detected using immunohistochemistry and immunofluorescence staining. The infarct volume was examined using 2,3,5-triphenyl tetrazolium chloride (TTC) staining, and the neurobehavioral progression was assessed using the neurological scoring system. The expression of astrocytes and microglia was detected using immunochemistry, and real-time quantitative PCR was used for the gene quantification of inflammatory cytokines. The extent of cerebral ischemia-reperfusion injury was tested using Nissl staining and the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay. The expression of the apoptotic proteins Bax, Bcl-2 and cleaved caspase-3 were detected using Western blot analysis, and the oxidative stress was also measured.
The expression of IL-11 mRNA and protein significantly decreased after cerebral ischemia. Immunohistochemical staining showed a large amount of IL-11 in the cerebral cortex of the mice in the vehicle group, whereas the immunoreactivity of IL-11 remained weak for 24 h in the MCAO group. Immunofluorescent staining further confirmed that IL-11 was mainly expressed in the neurons. It was suggested that IL-11 (20 μg/kg) treatment ameliorated infarction and reduced neurological scores. In addition, IL-11 proved to reduce neuropathic damage, glial activation, and the expression of proinflammatory cytokines and increase the expression of anti-inflammatory cytokines after cerebral ischemia. IL-11 was also able to alleviate oxidative stress caused by cerebral ischemia, and AMPK inhibition enhanced the alleviation. Moreover, IL-11 was found to inhibit apoptosis caused by cerebral ischemia, which could also be facilitated by AMPK inhibitors.
Our research suggests that IL-11 is decreased during cerebral ischemia-reperfusion injury, but IL-11 treatment can improve neurological function and reduce the cerebral infarct volume, which can trigger stroke in mice. AMPK inhibition can further promote the protective effect of IL-11 in stroke. Overall, we demonstrate that IL-11 is of therapeutic interest in controlling stroke and managing cerebral ischemia-reperfusion injury.
炎症和免疫反应是与中风发病和进展相关的关键因素。白细胞介素-11（IL-11）是一种造血细胞因子白细胞介素-6 家族，可作为针对各种炎症性疾病的抗炎剂。然而，其在中风中的作用尚不清楚。在本研究中，我们研究了 IL-11 对局灶性脑缺血模型中脑缺血再灌注损伤的影响。
将小鼠随机分为五组：载体组、大脑中动脉闭塞（MCAO）组、MCAO 加腺苷单磷酸激活蛋白激酶（AMPK）抑制剂化合物 C 组、MCAO 加 IL-11 治疗组和 MCAO 加 IL-11 治疗和化合物 C 组。通过闭塞左侧大脑中动脉诱导局灶性脑缺血，并在缺血后 2 小时通过拔出缝线实现再灌注。使用 Western blot 分析测量 IL-11 的蛋白表达水平，并使用免疫组织化学和免疫荧光染色检测其位置。使用 2,3,5-三苯基氯化四唑（TTC）染色检查梗死体积，并使用神经评分系统评估神经行为进展。使用免疫化学检测星形胶质细胞和小胶质细胞的表达，并使用实时定量 PCR 进行炎症细胞因子的基因定量。使用尼氏染色和末端脱氧核苷酸转移酶（TdT）介导的 dUTP 缺口末端标记（TUNEL）测定测试脑缺血再灌注损伤的程度。使用 Western blot 分析检测凋亡蛋白 Bax、Bcl-2 和 cleaved caspase-3 的表达，并测量氧化应激。
脑缺血后 IL-11 mRNA 和蛋白的表达显著降低。免疫组织化学染色显示载体组小鼠大脑皮质中大量的 IL-11，而 MCAO 组中 24 小时内 IL-11 的免疫反应性仍然较弱。免疫荧光染色进一步证实 IL-11 主要在神经元中表达。这表明 IL-11（20μg/kg）治疗可改善梗死并降低神经评分。此外，IL-11 可减少脑缺血后的神经病变损伤、神经胶质激活和促炎细胞因子的表达，并增加抗炎细胞因子的表达。IL-11 还可以减轻脑缺血引起的氧化应激，而 AMPK 抑制可增强这种缓解作用。此外，研究发现 IL-11 可抑制脑缺血引起的细胞凋亡，而 AMPK 抑制剂也可促进这种作用。
我们的研究表明，在脑缺血再灌注损伤期间，IL-11 减少，但 IL-11 治疗可以改善神经功能并减少脑梗死体积，这可能导致小鼠中风。AMPK 抑制可以进一步促进 IL-11 在中风中的保护作用。总体而言，我们证明 IL-11 具有控制中风和管理脑缺血再灌注损伤的治疗意义。
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