Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice.
Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice.
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DOI：
10.1161/strokeaha.115.010620
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发表时间：
2015-10
期刊：
影响因子：
8.3
通讯作者：
Doeppner TR
中科院分区：
文献类型：
--
作者：
Herz J;Sabellek P;Lane TE;Gunzer M;Hermann DM;Doeppner TR
炎症相关的共病有助于中风诱导的免疫反应和脑损伤。我们以前的研究表明，高脂血症加重缺血性脑损伤，这与外周和脑粒细胞数量增加有关。在此，我们评估了中性粒细胞对缺血性脑损伤加重的作用。将喂食正常食物的野生型小鼠和喂食高胆固醇饮食的ApoE敲除小鼠暴露于大脑中动脉闭塞（MCAO）。使用选择性拮抗剂SB 225002（2 mg/kg）或中和CXCR 2抗血清阻断CXCR 2。使用抗Ly 6 G抗体耗尽中性粒细胞。在缺血后72小时进行免疫组织化学、流式细胞术和实时PCR以确定脑组织损伤以及血液、骨髓和脑中的免疫学变化。在缺血后4、7和14天通过加速旋转杆和紧绳试验评估功能结果。CXCR 2去磷酸化减少了高脂血症ApoE−/−小鼠的神经功能缺损和梗死体积。中性粒细胞耗竭模拟了这种效应。CXCR 2拮抗剂可减轻高脂血症缺血时增加的脑中性粒细胞浸润和外周中性粒细胞增多。这种中性粒细胞反应的降低与骨髓中性粒细胞上的中性粒细胞凋亡增加和CXCR 2、iNOS和NOX 2表达水平降低相关。我们的数据表明中性粒细胞在高脂血症引起的缺血性脑损伤加重中的作用。因此，阻止中性粒细胞募集到脑中的CXCR 2阻断剂可能是患有高脂血症的患者的中风治疗的有效选择。
Inflammation-related co-morbidities contribute to stroke-induced immune responses and brain damage. We previously showed that hyperlipidemia exacerbates ischemic brain injury, which is associated with elevated peripheral and cerebral granulocyte numbers. Herein, we evaluate the contribution of neutrophils to the exacerbation of ischemic brain injury. Wildtype mice fed with a normal chow and ApoE knockout mice fed with a high cholesterol diet were exposed to middle cerebral artery occlusion (MCAO). CXCR2 was blocked using the selective antagonist SB225002 (2 mg/kg) or neutralizing CXCR2 antiserum. Neutrophils were depleted using an anti-Ly6G antibody. At 72 hours post-ischemia immunohistochemistry, flow cytometry and real-time PCR was performed to determine cerebral tissue injury and immunological changes in the blood, bone marrow and brain. Functional outcome was assessed by accelerated rota rod and tight rope tests at 4, 7 and 14 days post-ischemia. CXCR2 antagonization reduced neurological deficits and infarct volumes that were exacerbated in hyperlipidemic ApoE−/− mice. This effect was mimicked by neutrophil depletion. Cerebral neutrophil infiltration and peripheral neutrophilia, which were increased upon ischemia in hyperlipidemia, were attenuated by CXCR2 antagonization. This downscaling of neutrophil responses was associated with increased neutrophil apoptosis and reduced levels of CXCR2, iNOS and NOX2 expression on bone marrow neutrophils. Our data demonstrate a role of neutrophils in the exacerbation of ischemic brain injury induced by hyperlipidemia. Accordingly, CXCR2 blockade, which prevents neutrophil recruitment into the brain, might be an effective option for stroke treatment in patients suffering from hyperlipidemia.