TGFβ signalling plays an important role in IL4-induced alternative activation of microglia.
TGFβ signalling plays an important role in IL4-induced alternative activation of microglia.
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DOI：
10.1186/1742-2094-9-210
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发表时间：
2012-09-04
影响因子：
9.3
通讯作者：
Krieglstein K
中科院分区：
文献类型：
--
作者：
Zhou X;Spittau B;Krieglstein K
小胶质细胞是中枢神经系统的常驻免疫细胞，并被认为与多种神经退行性疾病有关。几项研究表明，小胶质细胞，像外周巨噬细胞，表现出两种完全不同的功能激活状态，称为经典（M1）和替代（M2）激活。TGFβ是最重要的抗炎细胞因子之一，其抑制小胶质细胞或巨噬细胞经典活化的作用已被广泛研究。然而，TGFβ在小胶质细胞交替激活过程中的作用尚未被描述。为了研究TGFβ在IL 4诱导的小胶质细胞交替激活中的作用，使用了来自新生C57 BL/6小鼠的BV 2以及原代小胶质细胞。采用定量RT-PCR和Western blot检测IL 4、TGFβ或两者联合作用后，替代活化标志物Arginase 1（Arg 1）和Chitinase 3-like 3（Ym 1）的mRNA和蛋白水平。采用水貂肺上皮细胞（MLEC）试验和直接TGFβ2 ELISA评价IL 4处理后内源性TGFβ的释放。应用TGFβ受体I型抑制剂和MAPK抑制剂来研究TGFβ信号和MAPK信号在IL 4诱导的小胶质细胞交替活化中的参与。TGFβ通过显著增加Arg 1和Ym 1的表达增强IL 4诱导的小胶质细胞交替激活。这种对Arg 1诱导的协同作用几乎完全被MAPK抑制剂PD 98059的应用阻断。此外，用IL 4处理原代小胶质细胞增加了TGFβ2的表达和分泌，表明内源性TGFβ参与了IL 4介导的小胶质细胞活化过程。此外，阻断TGFβ受体I后，IL 4介导的Arg 1和Ym 1诱导受损，表明IL 4诱导的小胶质细胞交替活化依赖于活性TGFβ信号传导。有趣的是，单独用TGFβ处理原代小胶质细胞导致IL 4受体α的上调，表明TGFβ增加了小胶质细胞对IL 4信号的敏感性。总之，我们的数据揭示了TGFβ在IL 4诱导的小胶质细胞交替激活过程中的新作用，并巩固了TGFβ作为小胶质细胞抗炎分子和免疫调节因子的基本功能。
Microglia are the resident immune cells of the central nervous system and are accepted to be involved in a variety of neurodegenerative diseases. Several studies have demonstrated that microglia, like peripheral macrophages, exhibit two entirely different functional activation states, referred to as classical (M1) and alternative (M2) activation. TGFβ is one of the most important anti-inflammatory cytokines and its effect on inhibiting microglia or macrophage classical activation has been extensively studied. However, the role of TGFβ during alternative activation of microglia has not been described yet. To investigate the role of TGFβ in IL4-induced microglia alternative activation, both, BV2 as well as primary microglia from new born C57BL/6 mice were used. Quantitative RT-PCR and western blots were performed to detect mRNA and protein levels of the alternative activation markers Arginase1 (Arg1) and Chitinase 3-like 3 (Ym1) after treatment with IL4, TGFβ or both. Endogenous TGFβ release after IL4 treatment was evaluated using the mink lung epithelial cell (MLEC) assay and a direct TGFβ2 ELISA. TGFβ receptor type I inhibitor and MAPK inhibitor were applied to address the involvement of TGFβ signalling and MAPK signalling in IL4-induced alternative activation of microglia. TGFβ enhances IL4-induced microglia alternative activation by strongly increasing the expression of Arg1 and Ym1. This synergistic effect on Arg1 induction is almost completely blocked by the application of the MAPK inhibitor, PD98059. Further, treatment of primary microglia with IL4 increased the expression and secretion of TGFβ2, suggesting an involvement of endogenous TGFβ in IL4-mediated microglia activation process. Moreover, IL4-mediated induction of Arg1 and Ym1 is impaired after blocking the TGFβ receptor I indicating that IL4-induced microglia alternative activation is dependent on active TGFβ signalling. Interestingly, treatment of primary microglia with TGFβ alone results in up regulation of the IL4 receptor alpha, indicating that TGFβ increases the sensitivity of microglia for IL4 signals. Taken together, our data reveal a new role for TGFβ during IL4-induced alternative activation of microglia and consolidate the essential functions of TGFβ as an anti-inflammatory molecule and immunoregulatory factor for microglia.
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影响因子：
2.9
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