Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons
Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons
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DOI：
10.1016/j.bbi.2018.11.012
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发表时间：
2019-02-01
影响因子：
15.1
通讯作者：
Allan, Stuart M.
中科院分区：
文献类型：
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作者：
Wong, Raymond;Lenart, Nikolett;Allan, Stuart M.
细胞因子白细胞介素-1（IL-1）是神经炎症和脑损伤的关键因素，但IL-1触发神经元损伤的机制仍不清楚。在这里，我们诱导条件删除IL-1 R1在脑内皮细胞，神经元和血细胞，以评估位点特异性IL-1的行动在小鼠脑缺血模型。他莫昔芬治疗IL-1 R1 floxed（（fl/fl））小鼠与在Slco 1c 1启动子下表达他莫昔芬诱导型Cre重组酶的小鼠杂交，导致脑内皮特异性IL-1 R1缺失，与溶媒治疗或对照（IL-1 R1（fl/fl））小鼠相比，梗死面积（29%）、血脑屏障（BBB）破坏（53%）和神经功能缺损（40%）显著减少。脑内皮细胞IL-1信号的缺乏改善脑血流量，其次是减少中性粒细胞浸润和血管活化脑损伤后24小时。使用他莫昔芬诱导的nestin-Cre小鼠在神经元中进行条件性IL-1 R1缺失导致神经元损伤减少（25%）和小胶质细胞-神经元相互作用改变，而不影响脑灌注或血管活化。特异性地在胆碱能神经元中缺失IL-1 R1可减少梗死面积、脑水肿并改善功能结果。IL-1 R1的普遍缺失对脑损伤没有影响，这表明对其他细胞的有益补偿机制对抗IL-1对内皮细胞和神经元的不利影响。我们还表明，血小板或骨髓细胞中IL-1 R1信号转导缺失不会导致实验性中风后的脑损伤。因此，脑内皮细胞和神经元（胆碱能）IL-1 R1介导缺血性中风中IL-1在脑中的有害作用。因此，脑中IL-1 R1的细胞特异性靶向可能对中风和其他脑血管疾病具有治疗益处。
The cytokine interleukin-1 (IL-1) is a key contributor to neuroinflammation and brain injury, yet mechanisms by which IL-1 triggers neuronal injury remain unknown. Here we induced conditional deletion of IL-1R1 in brain endothelial cells, neurons and blood cells to assess site-specific IL-1 actions in a model of cerebral ischaemia in mice. Tamoxifen treatment of IL-1R1 floxed ((fl/fl)) mice crossed with mice expressing tamoxifen-inducible Cre-recombinase under the Slco1c1 promoter resulted in brain endothelium-specific deletion of IL-1R1 and a significant decrease in infarct size (29%), blood-brain barrier (BBB) breakdown (53%) and neurological deficit (40%) compared to vehicle-treated or control (IL-1R1(fl/fl)) mice. Absence of brain endothelial IL-1 signalling improved cerebral blood flow, followed by reduced neutrophil infiltration and vascular activation 24 h after brain injury. Conditional IL-1R1 deletion in neurons using tamoxifen inducible nestin-Cre mice resulted in reduced neuronal injury (25%) and altered microglia-neuron interactions, without affecting cerebral perfusion or vascular activation. Deletion of IL-1R1 specifically in cholinergic neurons reduced infarct size, brain oedema and improved functional outcome. Ubiquitous deletion of IL-1R1 had no effect on brain injury, suggesting beneficial compensatory mechanisms on other cells against the detrimental effects of IL-1 on endothelial cells and neurons. We also show that IL-1R1 signalling deletion in platelets or myeloid cells does not contribute to brain injury after experimental stroke. Thus, brain endothelial and neuronal (cholinergic) IL-1R1 mediate detrimental actions of IL-1 in the brain in ischaemic stroke. Cell-specific targeting of IL-1R1 in the brain could therefore have therapeutic benefits in stroke and other cerebrovascular diseases.