Myeloid-specific deletion of the mineralocorticoid receptor reduces infarct volume and alters inflammation during cerebral ischemia.
Myeloid-specific deletion of the mineralocorticoid receptor reduces infarct volume and alters inflammation during cerebral ischemia.
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DOI：
10.1161/strokeaha.110.598441
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发表时间：
2011-01
期刊：
影响因子：
8.3
通讯作者：
Mortensen RM
中科院分区：
文献类型：
--
作者：
Frieler RA;Meng H;Duan SZ;Berger S;Schütz G;He Y;Xi G;Wang MM;Mortensen RM
盐皮质激素受体(MR)拮抗剂在缺血性卒中啮齿动物模型中具有保护作用，但这些药物的细胞类型特异性作用尚不清楚。在本研究中，我们利用髓系特异性MR基因敲除(MyMRKO)小鼠研究了髓系细胞MR在局灶性脑缺血中的作用。MyMRKO小鼠建立大脑中动脉短暂闭塞(MCAO)模型(n=5~7)，每组5~7只。用苏木精-伊红染色和图像分析软件对缺血脑梗塞进行定量。用IBA1染色对小胶质细胞和巨噬细胞进行免疫组织化学定位，用定量逆转录聚合酶链式反应(qRT-PCR)检测再灌流24 h后炎症标志物的表达。心肌梗死后脑梗塞体积缩小65%(P=0.005)。伴随而来的是缺血中心激活的小胶质细胞和巨噬细胞的显著减少。此外，MyMRKO抑制经典激活的M1巨噬细胞标志物肿瘤坏死因子α、IL-1β、MCP1、MIP1α和IL-6，而部分保留交替激活的M2标志物Arg1和YM1的诱导。这些数据表明，髓系MR的激活加剧了卒中，并将髓系MR确定为MR拮抗剂的关键靶点。此外，这些数据表明，MR激活在卒中炎症反应过程中控制免疫细胞功能具有重要作用。
Mineralocorticoid receptor (MR) antagonists have protective effects in rodent models of ischemic stroke, but the cell-type-specific actions of these drugs are unknown. In the present study, we examined the contribution of myeloid cell MR during focal cerebral ischemia using myeloid-specific MR knockout (MyMRKO) mice. MyMRKO mice were subjected to transient (90 minutes) middle cerebral artery occlusion (MCAo) followed by 24 hours reperfusion (n = 5–7/group). Ischemic cerebral infarcts were identified by hematoxylin and eosin staining and quantified with image analysis software. Immunohistochemical localization of microglia and macrophages was performed using Iba1 staining, and the expression of inflammatory markers was measured after 24 hours of reperfusion by qRT-PCR. MyMRKO resulted in a 65 % reduction in infarct volume (P = 0.005) following MCAo. This was accompanied by a significant reduction in activated microglia and macrophages in the ischemic core. Furthermore, MyMRKO suppressed classically activated M1 macrophage markers TNFα, IL-1β, MCP1, MIP1α and IL-6 while partially preserving the induction of alternatively activated, M2, markers Arg1 and Ym1. These data demonstrate that myeloid MR activation exacerbates stroke and identify myeloid MR as a critical target for MR antagonists. Further, these data indicate that MR activation has an important role in controlling immune cell function during the inflammatory response to stroke.