Microglia/Macrophage Polarization Dynamics Reveal Novel Mechanism of Injury Expansion After Focal Cerebral Ischemia
Microglia/Macrophage Polarization Dynamics Reveal Novel Mechanism of Injury Expansion After Focal Cerebral Ischemia
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DOI：
10.1161/strokeaha.112.659656
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发表时间：
2012-11-01
期刊：
影响因子：
8.3
通讯作者：
Chen, Jun
中科院分区：
文献类型：
--
作者：
Hu, Xiaoming;Li, Peiying;Chen, Jun
背景和目的-单核吞噬细胞是高度可塑性的细胞，可响应微环境信号而呈现不同的表型。小胶质细胞/巨噬细胞在缺血性脑损伤中的表型特异性作用尚不清楚。缺血后小胶质细胞/巨噬细胞极化的综合表征可能会增进我们对中风后损伤/恢复的认识。方法-在小鼠中诱导局灶性短暂性脑缺血 60 分钟；再灌注1至14天时对动物实施安乐死。对 M1 和 M2 标记物进行逆转录聚合酶链反应和免疫组织化学染色，以表征脑细胞（包括小胶质细胞和浸润巨噬细胞）的表型变化。使用Transwell系统、条件培养基转移系统或允许细胞间接触的共培养系统的体外实验进一步阐明神经元缺血对小胶质细胞/巨噬细胞极化的影响，以及相反，小胶质细胞/巨噬细胞表型对缺血神经元命运的影响。结果-局部小胶质细胞和新招募的巨噬细胞在缺血性中风的早期呈现M2表型，但逐渐转变进入梗塞周围区域的 M1 表型。体外实验表明，缺血神经元会引发小胶质细胞向 M1 表型极化。 M1 极化的小胶质细胞或 M1 条件培养基加剧了缺氧葡萄糖诱导的神经元死亡。相反，维持小胶质细胞的 M2 表型可以保护神经元免受氧葡萄糖剥夺的影响。结论 - 我们的结果表明，小胶质细胞/巨噬细胞对缺血性损伤做出动态反应，经历早期“健康”M2 表型，然后过渡到“病态”M1 表型。小胶质细胞/巨噬细胞的这些双重且相反的作用表明，中风治疗应该从简单地抑制小胶质细胞/巨噬细胞转向调整
Background and Purpose-Mononuclear phagocytes are highly plastic cells that assume diverse phenotypes in response to microenvironmental signals. The phenotype-specific roles of microglia/macrophages in ischemic brain injury are poorly understood. A comprehensive characterization of microglia/macrophage polarization after ischemia may advance our knowledge of poststroke damage/recovery.Methods-Focal transient cerebral ischemia was induced in mice for 60 minutes; animals were euthanized at 1 to 14 days of reperfusion. Reverse-transcriptase polymerase chain reaction and immunohistochemical staining for M1 and M2 markers were performed to characterize phenotypic changes in brain cells, including microglia and infiltrating macrophages. In vitro experiments using a transwell system, a conditioned medium transfer system, or a coculture system allowing cell-to-cell contacts were used to further elucidate the effect of neuronal ischemia on microglia/macrophage polarization and, conversely, the effect of microglia/macrophage phenotype on the fate of ischemic neurons.Results-Local microglia and newly recruited macrophages assume the M2 phenotype at early stages of ischemic stroke but gradually transformed into the M1 phenotype in peri-infarct regions. In vitro experiments revealed that ischemic neurons prime microglial polarization toward M1 phenotype. M1-polarized microglia or M1-conditioned media exacerbated oxygen glucose deprivation-induced neuronal death. In contrast, maintaining the M2 phenotype of microglia protected neurons against oxygen glucose deprivation.Conclusions-Our results suggest that microglia/macrophages respond dynamically to ischemic injury, experiencing an early "healthy" M2 phenotype, followed by a transition to a "sick" M1 phenotype. These dual and opposing roles of microglia/macrophages suggest that stroke therapies should be shifted from simply suppressing microglia/macrophage toward adjusting the