Department of Brain Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Glia. 2011 Feb;59(2):242-55. doi: 10.1002/glia.21094.
There is increasing evidence that astrocytes play important roles in immune regulation in the brain. Astrocytes express toll-like receptors (TLR) and build up responses to innate immune triggers by releasing proinflammatory molecules. We investigate signaling pathways and released molecules after astrocyte TLR4 activation. Purified rodent brain astrocyte cultures were treated with the TLR4 activator bacterial lipopolysaccharide (LPS). Tools used to interfere with this system include small interference RNA, inhibitory drugs, and MyD88 or Stat1 deficient mice. LPS induced early activation of the transcription factor NFκB, through the MyD88 adaptor, and expression of TNF-α, VCAM-1, IL-15, and IL-27. LPS also induced delayed Jak1/Stat1 activation, which was MyD88-independent but was not mediated by IFN-β. Jak1/Stat1 activation induced the expression of negative cytokine regulator SOCS-1 and CXCL10 chemokine (IP-10). Mitogen-activated protein kinases (MAPK) were also involved in TLR4 signaling in a MyD88-independent fashion. p38 exerted a strong influence on LPS-induced gene expression by regulating the phosphorylation of Stat1 and the transcriptional activity of NFκB, while JNK regulated the Jak1/Stat1 pathway, and ERK1/2 controlled the expression of Egr-1 and influenced MyD88-dependent MMP-9 expression. Interplay between these signals was evidenced by the increased induction of MMP-9 in Stat1-deficient cells challenged with LPS, suggesting that Stat1 negatively regulates the expression of MMP-9 induced by LPS. Therefore, astrocytes are responsive to TLR4 activation by inducing a complex set of cell-dependent molecular reactions mediated by NFκB, MAPK and Jak1/Stat1 signaling pathways. Here we identified cross-talking signals generating a proinflammatory environment that will modulate the response of surrounding cells.
越来越多的证据表明星形胶质细胞在大脑免疫调节中发挥重要作用。星形胶质细胞表达 Toll 样受体 (TLR)，并通过释放促炎分子对先天免疫触发物产生反应。我们研究了星形胶质细胞 TLR4 激活后的信号通路和释放的分子。用 TLR4 激活剂细菌脂多糖 (LPS) 处理纯化的啮齿动物脑星形胶质细胞培养物。用于干扰该系统的工具包括小干扰 RNA、抑制性药物、MyD88 或 Stat1 缺陷小鼠。LPS 通过 MyD88 衔接蛋白诱导转录因子 NFκB 的早期激活，并诱导 TNF-α、VCAM-1、IL-15 和 IL-27 的表达。LPS 还诱导 Jak1/Stat1 的延迟激活，该激活不依赖于 MyD88，但不通过 IFN-β介导。Jak1/Stat1 激活诱导负细胞因子调节剂 SOCS-1 和趋化因子 CXCL10（IP-10）的表达。丝裂原活化蛋白激酶 (MAPK) 也以 MyD88 非依赖性方式参与 TLR4 信号转导。p38 通过调节 Stat1 的磷酸化和 NFκB 的转录活性对 LPS 诱导的基因表达产生强烈影响，而 JNK 调节 Jak1/Stat1 途径，ERK1/2 控制 Egr-1 的表达并影响 MyD88 依赖性 MMP-9 的表达。这些信号之间的相互作用通过在 LPS 挑战下 Stat1 缺陷细胞中 MMP-9 的诱导增加得到证实，表明 Stat1 负调节 LPS 诱导的 MMP-9 表达。因此，星形胶质细胞通过诱导 NFκB、MAPK 和 Jak1/Stat1 信号通路介导的一组复杂的细胞依赖性分子反应对 TLR4 激活作出反应。在这里，我们确定了产生促炎环境的交叉对话信号，该环境将调节周围细胞的反应。
