Inhibition of CD147 (Cluster of Differentiation 147) Ameliorates Acute Ischemic Stroke in Mice by Reducing Thromboinflammation.
Inhibition of CD147 (Cluster of Differentiation 147) Ameliorates Acute Ischemic Stroke in Mice by Reducing Thromboinflammation.
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DOI：
10.1161/strokeaha.117.018839
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发表时间：
2017-12
期刊：
影响因子：
8.3
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Jin R;Xiao AY;Chen R;Granger DN;Li G
炎症和血栓形成是目前公认的缺血性脑卒中发病机制的关键因素。CD147，也被称为细胞外基质金属蛋白酶诱导剂，可以作为炎症和免疫反应的关键介质。脑缺血后，CD147在脑中的表达增加，但其在缺血性脑卒中发病机制中的作用尚不清楚。在这项研究中，我们发现CD147通过驱动血栓和炎症反应在缺血性卒中中发挥关键作用。C57BL/6小鼠经大脑中动脉阻断60 min诱导局灶性脑缺血。用抗cd147功能阻断抗体（αCD147）或同型对照抗体处理。缺血24小时后，观察血脑屏障通透性、血栓形成及微血管通畅程度。缺血72小时后评估梗死面积、神经功能缺损和脑内浸润的炎症细胞。缺血脑内皮细胞CD147表达迅速升高。抑制CD147可减少梗死面积并改善tMCAO后第3天的功能结果。其神经保护作用与以下因素有关：1)防止血脑屏障损伤；2)减少血管内纤维蛋白和血小板沉积，从而减少血栓形成和增加脑灌注；3)减少脑炎性细胞浸润。其潜在机制可能包括降低脑微血管内皮细胞中核因子NF-κB活化、基质金属蛋白酶-9 （MMP-9）活性和纤溶酶原激活物抑制剂-1 （PAI-1）的表达。抑制CD147通过减少血栓炎症改善急性缺血性卒中。CD147可能是缺血性卒中和其他可能的血栓炎性疾病的一个新的和有前途的治疗靶点。
Inflammation and thrombosis currently are recognized as critical contributors to the pathogenesis of ischemic stroke. CD147, also known as extracellular matrix metalloproteinase inducer, can function as a key mediator of inflammatory and immune responses. CD147 expression is increased in the brain after cerebral ischemia, but its role in the pathogenesis of ischemic stroke remains unknown. In this study, we show that CD147 acts as a key player in ischemic stroke by driving thrombotic and inflammatory responses. Focal cerebral ischemia was induced in C57BL/6 mice by a 60-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with anti-CD147 function blocking antibody (αCD147) or isotype control antibody. Blood-brain barrier permeability, thrombus formation, and microvascular patency were assessed 24h after ischemia. Infarct size, neurological deficits, and inflammatory cells invaded in the brain were assessed 72 hours after ischemia. CD147 expression was rapidly increased in ischemic brain endothelium after tMCAO. Inhibition of CD147 reduced infarct size and improved functional outcome on day 3 after tMCAO. The neuroprotective effects were associated with 1) prevented BBB damage, 2) decreased intravascular fibrin- and platelet- deposition, which in turn reduced thrombosis and increased cerebral perfusion, and 3) reduced brain inflammatory cell infiltration. The underlying mechanism may include reduced nuclear factor NF-κB activation, matrix metalloproteinase-9 (MMP-9) activity, and plasminogen activator inhibitor-1 (PAI-1) expression in brain microvascular endothelial cells. Inhibition of CD147 ameliorates acute ischemic stroke by reducing thrombo-inflammation. CD147 might represent a novel and promising therapeutic target for ischemic stroke and possibly other thrombo-inflammatory disorders.