Microglial Cells Contribute to Endogenous Brain Defenses after Acute Neonatal Focal Stroke

被引:235
|
作者
Faustino, Joel V. [1 ]
Wang, Xia [1 ,3 ]
Johnson, Cali E. [1 ]
Klibanov, Alexander [4 ]
Derugin, Nikita [1 ]
Wendland, Michael F. [2 ]
Vexler, Zinaida S. [1 ]
机构
[1] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA
[3] Cent S Univ, Xiangya Hosp, Dept Pediat, Changsha 410008, Hunan, Peoples R China
[4] Univ Virginia, Dept Med, Charlottesville, VA 22908 USA
来源
JOURNAL OF NEUROSCIENCE | 2011年 / 31卷 / 36期
关键词
HYPOXIA-ISCHEMIA; CEREBRAL-ISCHEMIA; APOPTOTIC CELLS; HYDROGEN-PEROXIDE; OXIDATIVE STRESS; NADPH OXIDASE; LIPID RAFTS; MOUSE-BRAIN; ACTIVATION; MACROPHAGES;
D O I
10.1523/JNEUROSCI.2102-11.2011
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Macrophages are viewed as amplifiers of ischemic brain injury, but the origin of injury-producing macrophages is poorly defined. The role of resident brain macrophages-microglial cells-in stroke remains controversial. To determine whether microglial cells exert injurious effects after neonatal focal stroke, we selectively depleted these cells with intracerebral injection of liposome-encapsulated clodronate before transient middle cerebral artery occlusion in postnatal day 7 rats. Phagocytosis of apoptotic neurons by activated microglia was poor in animals with unmanipulated microglia, and depletion of these cells did not increase the number of apoptotic neurons. Lack of microglia increased the brain levels of several cytokines and chemokines already elevated by ischemia-reperfusion, and also increased the severity and volume of injury, suggesting that microglial cells contribute to endogenous protection during the subacute injury phase. Then, to determine whether accumulation of reactive oxygen species in microglia adversely affects phagocytosis of dying neurons and contributes to injury, we delivered reduced glutathione (GSH) into microglia, again using liposomes. Remarkably, pharmacologically increased intracellular GSH concentrations in microglia induced superoxide accumulation in lipid rafts in these cells, further increased the brain levels of macrophage chemoattractants, and exacerbated injury. Together, these data show that microglia are part of the endogenous defense mechanisms and that, while antioxidants can protect the injured neonatal brain, high levels of reducing equivalents in activated microglia, GSH, trigger superoxide production, favor the reorganization of lipids, amplify local inflammation and exacerbate injury.
引用
收藏
页码:12992 / 13001
页数:10
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