Inflammatory mediators alter the astrocyte transcriptome and calcium signaling elicited by multiple G-protein-coupled receptors.
Inflammatory mediators alter the astrocyte transcriptome and calcium signaling elicited by multiple G-protein-coupled receptors.
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DOI：
10.1523/jneurosci.1256-12.2012
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发表时间：
2012-10-17
期刊：
影响因子：
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通讯作者：
Sofroniew MV
中科院分区：
文献类型：
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作者：
Hamby ME;Coppola G;Ao Y;Geschwind DH;Khakh BS;Sofroniew MV
中枢神经系统疾病（如中风、创伤、神经变性、感染和自身免疫）中的炎症特征，其中星形胶质细胞发挥关键作用。为了阐明炎症介质如何改变星形胶质细胞的功能，我们检测了转化生长因子-β1（TGF-β1）、脂多糖（LPS）和干扰素-γ（IFNγ）单独和联合对纯化的小鼠原代皮质星形胶质细胞培养物的影响。我们使用微阵列进行全基因组表达谱分析，并测量钙信号，这是在介导动态星形胶质细胞功能。组合暴露于TGF-β1、LPS和IFNγ可显著调节星形胶质细胞表达>6800个基因探针，包括>380个未通过加总个体处理效应预测的协同变化。生物信息学分析揭示了显著和显著上调的分子网络和途径，特别是与免疫信号传导和细胞损伤、死亡、生长和增殖的调节相关的分子网络和途径。高度调控的基因包括趋化因子、生长因子、酶、通道、转运蛋白、细胞间和细胞内信号转导子。值得注意的是，参与钙信号传导的G蛋白偶联受体（GPCR）和G蛋白效应子的许多基因被显著调节，大多数下调（例如，Cxcr 4、Adra 2a、Ednra、P2 y1、Gnao 1、Gng 7），但也有一些上调（例如，P2 y14、P2 y 6、Ccrl 2、Gnb 4）。我们对选定的病例进行了测试，发现GPCR基因表达的变化伴随着相应GPCR特异性配体诱发的星形胶质细胞钙信号的显著平行变化。这些发现确定了TGF-β1、LPS和IFNγ诱导的星形胶质细胞转录组的显著变化，并表明这些炎症刺激上调了与免疫和损伤相关功能相关的星形胶质细胞分子网络，并显著改变了多种GPCR刺激的星形胶质细胞钙信号传导。
Inflammation features in CNS disorders such as stroke, trauma, neurodegeneration, infection, and autoimmunity in which astrocytes play critical roles. To elucidate how inflammatory mediators alter astrocyte functions, we examined effects of transforming growth factor-β1 (TGF-β1), lipopolysaccharide (LPS), and interferon-gamma (IFNγ), alone and in combination, on purified, mouse primary cortical astrocyte cultures. We used microarrays to conduct whole-genome expression profiling, and measured calcium signaling, which is implicated in mediating dynamic astrocyte functions. Combinatorial exposure to TGF-β1, LPS, and IFNγ significantly modulated astrocyte expression of >6800 gene probes, including >380 synergistic changes not predicted by summing individual treatment effects. Bioinformatic analyses revealed significantly and markedly upregulated molecular networks and pathways associated in particular with immune signaling and regulation of cell injury, death, growth, and proliferation. Highly regulated genes included chemokines, growth factors, enzymes, channels, transporters, and intercellular and intracellular signal transducers. Notably, numerous genes for G-protein-coupled receptors (GPCRs) and G-protein effectors involved in calcium signaling were significantly regulated, mostly down (for example, Cxcr4, Adra2a, Ednra, P2y1, Gnao1, Gng7), but some up (for example, P2y14, P2y6, Ccrl2, Gnb4). We tested selected cases and found that changes in GPCR gene expression were accompanied by significant, parallel changes in astrocyte calcium signaling evoked by corresponding GPCR-specific ligands. These findings identify pronounced changes in the astrocyte transcriptome induced by TGF-β1, LPS, and IFNγ, and show that these inflammatory stimuli upregulate astrocyte molecular networks associated with immune- and injury-related functions and significantly alter astrocyte calcium signaling stimulated by multiple GPCRs.