Institute for Anatomy and Cell Biology, Department of Molecular Embryology, Albert-Ludwigs-University, Freiburg, Germany.
Glia. 2013 Feb;61(2):287-300. doi: 10.1002/glia.22435. Epub 2012 Oct 12.
Microglia are the immune cells of the central nervous system (CNS) and play important roles under physiological and pathophysiological conditions. Activation of microglia has been reported for a variety of CNS diseases and is believed to be involved in inflammation-mediated neurodegeneration. Loss of TGFβ1 results in increased microgliosis and neurodegeneration in mice which indicates that TGFβ1 is an important regulator of microglial functions in vivo. Here, we addressed the role of endogenous TGFβ signaling for microglia in vitro. We clearly demonstrate active TGFβ signaling in primary microglia and further introduce Klf10 as a new TGFβ target gene in microglia. Moreover, we provide evidence that microglia express and release TGFβ1 that acts in an autocrine manner to activate microglial TGFβ/Smad signaling in vitro. Using microarrays, we identified TGFβ-regulated genes in microglia that are involved in TGFβ1 processing, its extracellular storage as well as activation of latent TGFβ. Finally, we demonstrate that pharmacological inhibition of microglial TGFβ signaling resulted in upregulation of the proinflammatory markers IL6 and iNOS and downregulation of the alternative activation markers Arg1 and Ym1 in vitro. Together, these data clearly show that endogenous TGFβ1 and autocrine TGFβ signaling is important for microglial quiescence in vitro and further suggest the upregulation of TGFβ1 in neurodegenerative diseases as a mechanism to regulate microglia functions and silence neuroinflammation.
小胶质细胞是中枢神经系统 (CNS) 的免疫细胞，在生理和病理生理条件下发挥重要作用。已经报道了小胶质细胞的激活与多种 CNS 疾病有关，并且被认为参与了炎症介导的神经退行性变。TGFβ1 的缺失会导致小鼠小胶质细胞增生和神经退行性变增加，这表明 TGFβ1 是体内小胶质细胞功能的重要调节剂。在这里，我们研究了内源性 TGFβ 信号对体外小胶质细胞的作用。我们清楚地证明了原代小胶质细胞中存在活跃的 TGFβ 信号，并进一步介绍了 Klf10 作为小胶质细胞中 TGFβ 的新靶基因。此外，我们提供的证据表明，小胶质细胞表达并释放 TGFβ1，以自分泌方式在体外激活小胶质细胞 TGFβ/Smad 信号。通过微阵列分析，我们鉴定了小胶质细胞中 TGFβ 调节的基因，这些基因参与 TGFβ1 的加工、其细胞外储存以及潜伏 TGFβ 的激活。最后，我们证明了在体外抑制小胶质细胞 TGFβ 信号会导致促炎标志物 IL6 和 iNOS 的上调，以及替代激活标志物 Arg1 和 Ym1 的下调。总之，这些数据清楚地表明，内源性 TGFβ1 和自分泌 TGFβ 信号对体外小胶质细胞的静止状态很重要，并进一步表明神经退行性疾病中 TGFβ1 的上调是调节小胶质细胞功能和沉默神经炎症的一种机制。
