Regulator of G Protein Signaling 10 (Rgs10) Expression Is Transcriptionally Silenced in Activated Microglia by Histone Deacetylase Activity
Regulator of G Protein Signaling 10 (Rgs10) Expression Is Transcriptionally Silenced in Activated Microglia by Histone Deacetylase Activity
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DOI：
10.1124/mol.116.106963
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发表时间：
2017-03-01
影响因子：
3.6
通讯作者：
Hooks, Shelley B.
中科院分区：
文献类型：
--
作者：
Alqinyah, Mohammed;Maganti, Nagini;Hooks, Shelley B.
RGS 10已成为小胶质细胞中促炎细胞因子产生的关键调节因子，作为重要的神经保护因子发挥作用。虽然RGS 10通常在小胶质细胞中以高水平表达，但在TLR 4受体活化后，表达在体外沉默。鉴于RGS 10调节炎症信号传导的能力，小胶质细胞中RGS 10水平的动态调节可能是调节炎症反应的重要机制。本研究的目的是证实RGS 10在小胶质细胞活化的体内炎症模型中受到抑制，并确定小胶质细胞中Rgs 10表达的活化依赖性沉默机制。我们证明，内源性RGS 10存在于脊髓小胶质细胞，和RGS 10蛋白水平被抑制在脊髓神经损伤诱导的神经性疼痛小鼠模型。我们发现，组蛋白脱乙酰酶（HDAC）酶抑制剂阿司他丁阻断脂多糖（LPS）抑制Rgs 10在BV-2和初级小胶质细胞转录的能力，表明HDAC酶是LPS沉默Rgs 10所必需的。此外，我们使用染色质免疫沉淀证明，在BV-2小胶质细胞LPS激活后，Rgs 10近端启动子处的H3组蛋白被脱乙酰化，LPS刺激后，Rgs 10启动子处的HDAC 1结合增强。最后，我们已经表明，鞘氨醇1-磷酸，内源性小胶质细胞信号介质，抑制HDAC活性，增强BV-2小胶质细胞的基础Rgs 10的表达，表明Rgs 10的表达是动态调节小胶质细胞在响应多种信号。
RGS10 has emerged as a key regulator of proinflammatory cytokine production in microglia, functioning as an important neuroprotective factor. Although RGS10 is normally expressed in microglia at high levels, expression is silenced in vitro following activation of TLR4 receptor. Given the ability of RGS10 to regulate inflammatory signaling, dynamic regulation of RGS10 levels in microglia may be an important mechanism to tune inflammatory responses. The goals of the current study were to confirm that RGS10 is suppressed in an in vivo inflammatory model of microglial activation and to determine the mechanism for activation- dependent silencing of Rgs10 expression in microglia. We demonstrate that endogenous RGS10 is present in spinal cord microglia, and RGS10 protein levels are suppressed in the spinal cord in a nerve injury-induced neuropathic pain mouse model. We show that the histone deacetylase (HDAC) enzyme inhibitor trichostatin A blocks the ability of lipopolysaccharide (LPS) to suppress Rgs10 transcription in BV-2 and primary microglia, demonstrating that HDAC enzymes are required for LPS silencing of Rgs10. Furthermore, we used chromatin immunoprecipitation to demonstrate that H3 histones at the Rgs10 proximal promoter are deacetylated in BV-2 microglia following LPS activation, and HDAC1 association at the Rgs10 promoter is enhanced following LPS stimulation. Finally, we have shown that sphingosine 1-phosphate, an endogenous microglial signaling mediator that inhibits HDAC activity, enhances basal Rgs10 expression in BV-2 microglia, suggesting that Rgs10 expression is dynamically regulated in microglia in response to multiple signals.