Effector molecules released by Th1 but not Th17 cells drive an M1 response in microglia
Effector molecules released by Th1 but not Th17 cells drive an M1 response in microglia
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DOI：
10.1016/j.bbi.2014.01.001
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发表时间：
2014-03-01
影响因子：
15.1
通讯作者：
Stangel, Martin
中科院分区：
文献类型：
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作者：
Prajeeth, Chittappen K.;Loehr, Kirsten;Stangel, Martin
小胶质细胞在中枢神经系统（CNS）中充当炎症传感器并对许多刺激做出反应。神经炎性疾病的其他关键参与者是CD 4（+）T辅助细胞（Th）亚群，其特征性地分泌IFN-γ（Th 1）或IL-17（Th 17）。然而，这些效应T细胞亚群产生的不同细胞因子环境调节小胶质细胞表型和功能的潜力知之甚少。因此，我们研究了Th 1和Th 17细胞分泌的因子诱导小胶质细胞活化的能力。在体外实验中，其中小胶质细胞培养的存在下，来自极化的Th 1或Th 17培养物的上清液，揭示了Th 1相关因子可以直接激活和触发的促炎性M1型基因表达谱的小胶质细胞是细胞-细胞接触无关，而Th 17细胞或其相关因子没有任何直接的影响小胶质细胞。为了评估关键Th 17效应细胞因子IL-17 A在体内的作用，我们使用了其中IL-17 A在星形胶质细胞中特异性表达的转基因小鼠。流式细胞术和组织学分析显示，小胶质细胞的表型只有细微的变化，表明组成型产生的IL-17 A对体内小胶质细胞的影响很小。IL-23信号传导和GM-CSF（最近描述的Th 17细胞的效应分子）的添加都没有改变Th 17细胞活化小胶质细胞的能力。这些发现证明了Th 1细胞对小胶质细胞的有效作用，然而，Th 17细胞如何在CNS炎症中实现其作用的机制仍不清楚。(C)2014 Elsevier Inc. All rights reserved.
Microglia act as sensors of inflammation in the central nervous system (CNS) and respond to many stimuli. Other key players in neuroinflammatory diseases are CD4(+) T helper cell (Th) subsets that characteristically secrete IFN-gamma (Th1) or IL-17 (Th17). However, the potential of a distinct cytokine milieu generated by these effector T cell subsets to modulate microglial phenotype and function is poorly understood. We therefore investigated the ability of factors secreted by Th1 and Th17 cells to induce microglial activation. In vitro experiments wherein microglia were cultured in the presence of supernatants derived from polarized Th1 or Th17 cultures, revealed that Th1-associated factors could directly activate and trigger a proinflammatory M1-type gene expression profile in microglia that was cell-cell contact independent, whereas Th17 cells or its associated factors did not have any direct influence on microglia. To assess the effects of the key Th17 effector cytokine IL-17A in vivo we used transgenic mice in which IL-17A is specifically expressed in astrocytes. Flow cytometric and histological analysis revealed only subtle changes in the phenotype of microglia suggesting only minimal effects of constitutively produced IL-17A on microglia in vivo. Neither IL-23 signaling nor addition of GM-CSF, a recently described effector molecule of Th17 cells, changed the incapacity of Th17 cells to activate microglia. These findings demonstrate a potent effect of Th1 cells on microglia, however, the mechanism of how Th17 cells achieve their effect in CNS inflammation remains unclear. (C) 2014 Elsevier Inc. All rights reserved.