mTOR Signaling Inhibition Modulates Macrophage/Microglia-Mediated Neuroinflammation and Secondary Injury via Regulatory T Cells after Focal Ischemia

作者：Xie, Luokun; Sun, Fen; Wang, Jixian; Mao, XiaoOu; Xie, Lin; Yang, Shao-Hua; Su, Dong-Ming; Simpkins, James W.; Greenberg, David A.; Jin, Kunlin^*

来源：The Journal of Immunology, 2014, 192(12): 6009-6019.

DOI：10.4049/jimmunol.1303492

• MONOCYTE CHEMOATTRACTANT PROTEIN-1
• INTERLEUKIN-1-BETA MESSENGER-RNA
• FACTOR-ALPHA EXPRESSION
• CEREBRAL-ISCHEMIA
• INFLAMMATORY MECHANISMS
• PLASMINOGEN-ACTIVATOR
• RAPAMYCIN PROTECTS
• DENDRITIC CELLS
• STROKE
• IL-2

Signaling by the mammalian target of rapamycin (mTOR) plays an important role in the modulation of both innate and adaptive immune responses. However, the role and underlying mechanism of mTOR signaling in poststroke neuroinflammation are largely unexplored. In this study, we injected rapamycin, a mTOR inhibitor, by the intracerebroventricular route 6 h after focal ischemic stroke in rats. We found that rapamycin significantly reduced lesion volume and improved behavioral deficits. Notably, infiltration of gamma delta T cells and granulocytes, which are detrimental to the ischemic brain, was profoundly reduced after rapamycin treatment, as was the production of proinflammatory cytokines and chemokines by macrophages and microglia. Rapamycin treatment prevented brain macrophage polarization toward the M1 type. In addition, we also found that rapamycin significantly enhanced antiinflammation activity of regulatory T cells (Tregs), which decreased production of proinflammatory cytokines and chemokines by macrophages and microglia. Depletion of Tregs partially elevated macrophage/microglia-induced neuroinflammation after stroke. Our data suggest that rapamycin can attenuate secondary injury and motor deficits after focal ischemia by enhancing the antiinflammation activity of Tregs to restrain poststroke neuroinflammation.

• 出版日期2014-6-15
• 单位上海市闵行区中心医院; 上海交通大学