Mesencephalic astrocyte-derived neurotrophic factor restores blood-brain barrier integrity of aged mice after ischaemic stroke/reperfusion through anti-inflammation via TLR4/MyD88/NF-kappa B pathway
Mesencephalic astrocyte-derived neurotrophic factor restores blood-brain barrier integrity of aged mice after ischaemic stroke/reperfusion through anti-inflammation via TLR4/MyD88/NF-kappa B pathway
复制标题
中脑星形胶质细胞源性神经营养因子通过 TLR4/MyD88/NF-κB 通路抗炎恢复缺血性中风/再灌注后老年小鼠的血脑屏障完整性
DOI：
10.1080/1061186x.2021.2003803
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发表时间：
2021-11-17
影响因子：
4.5
通讯作者：
Wang, Siliang
中科院分区：
文献类型：
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作者：
Han, Dan;Li, Fengyang;Wang, Siliang
缺血性卒中仍然是全球残疾和死亡的主要原因，老年患者的衰老相关炎症特别导致卒中后血脑屏障（BBB）破坏比年轻受试者更严重。因此，抑制过度炎症可以减轻BBB损伤，这为老年缺血性脑卒中提供了潜在的治疗方法。以往的研究表明，中脑星形胶质细胞源性神经营养因子（MANF）调节炎症反应，减轻肝脏损伤的老化。然而，目前尚不清楚MANF是否赋予缺血性脑卒中老年小鼠BBB类似的益处。在老年小鼠（18-20月龄）中进行大脑中动脉闭塞（MCAO）诱导的短暂脑缺血。MCAO后2 h右侧脑室注射MANF。观察脑缺血后72 h血脑屏障完整性、紧密连接蛋白、微血管超微结构、梗死体积、神经功能评分、脑含水量、促炎细胞因子和中性粒细胞浸润率。在体外研究中，应用H2 O2诱导的衰老bEnd.3细胞来探讨可能的机制。首先，我们证实，缺血性中风/再灌注在衰老条件下促进脑内皮细胞上的MANF的过度表达。补充MANF可抑制促炎因子的产生，恢复血脑屏障的完整性，从而减轻梗死体积、神经功能评分、脑含水量和中性粒细胞浸润率。此外，MANF通过干预促炎因子的产生，维持了老年缺血性脑卒中后依赖于TLR 4/MyD 88/NF-κ B通路的BB B的完整性。总之，认识到MANF在老年条件下BBB破坏过程中的作用，可能为缺血性脑卒中的治疗提供新的途径。
Ischaemic stroke remains a leading cause of disability and mortality worldwide and ageing-associated inflammation for the aged patients specifically leads to worse post-stroke blood-brain barrier (BBB) disruption than young subjects. Accordingly, suppression of excessive inflammation can alleviate BBB injury, which provides potential therapeutic treatment for ischaemic stroke of the aged. Prior studies revealed that mesencephalic astrocyte-derived neurotrophic factor (MANF) regulated inflammatory response and alleviated liver injury in ageing. However, it is unclear whether MANF confer similar benefit to BBB of aged mice suffered from ischaemic stroke. Transient cerebral ischaemia induced by middle cerebral artery occlusion (MCAO) was conducted in aged mice (18-20 months old). MANF was injected into the right lateral ventricle 2 h after MCAO. BBB integrity, tight junctional proteins, ultrastructure of microvessels, infarct volume, neurological scores, brain water content, pro-inflammatory cytokines and neutrophil infiltration rate were determined 72 h after MCAO. H2O2-induced senescent bEnd.3 cells were applied in the in vitro study to investigate the possible mechanism. First, we confirmed that ischaemic stroke/reperfusion in senescent condition promoted the over-expression of MANF on brain endothelial cells. Then, MANF supplement could suppress the pro-inflammatory factor production, restore BBB integrity and then alleviate infarct volume, neurological scores, brain water content and neutrophil infiltration rate. In addition, MANF maintained BBB integrity after ischaemic stroke of aged condition dependent on TLR4/MyD88/NF-kappa B pathway via intervention of pro-inflammatory factors production. In summary, the recognition of MANF in the process of BBB breakdown at aged condition may offer novel therapeutic approaches for ischaemic stroke.