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首页> 外文期刊>European Journal of Cell Biology: Journal of Deutsche Gesellschaft fur Elektronenmikroskopie: Journal of Deutsche Gesellschaft fur Zellbiologie >Incretin hormones regulate microglia oxidative stress, survival and expression of trophic factors
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Incretin hormones regulate microglia oxidative stress, survival and expression of trophic factors

机译：Incetin激素调节小凝血性氧化应激，存活率和营养因素的表达

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摘要

The incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are primarily known for their metabolic function in the periphery. GLP-1 and GIP are secreted by intestinal endocrine cells in response to ingested nutrients. Both GLP-1 and GIP stimulate the production and release of insulin from pancreatic (3 cells as well as exhibit several growth-regulating effects on peripheral tissues. GLP-1 and GIP are also present in the brain, where they provide modulatory and antiapoptotic signals to neurons. However, very limited information is available regarding the effects of these hormones on glia, the immune and supporting cells of the brain. Therefore, we set out to resolve whether primary human microglia and astrocytes, two subtypes of glial cells, express the GLP-1 receptor (GLP-1R) and GIP receptor (GIPR), which are necessary to detect and respond to GLP-1 and GIP, respectively. We further tested whether these hormones, similar to their effects on neuronal cells, have growth-regulating, antioxidant and anti-apoptotic effects on microglia. We show for the first time expression of the GLP-1R and the GIPR by primary human microglia and astrocytes. We demonstrate that GLP-1 and GIP reduce apoptotic death of murine BV-2 microglia through the binding and activation of the GLP-1R and GIPR, respectively, with subsequent activation of the protein kinase A (PKA) pathway. Moreover, we reveal that incretins upregulate BV-2 microglia expression of brain derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF) and nerve growth factor (NGF) in a phosphoinositide 3-kinase (PI3K)- and MA-dependent manner. We also show that incretins reduce oxidative stress in BV-2 microglia by inhibiting the accumulation of intracellular reactive oxygen species (ROS) and release of nitric oxide (NO), as well as by increasing the expression of the antioxidant glutathione peroxidase 1 (GPx1) and superoxide dismutase 1 (SOD1). We confirm these results by demonstrating that GLP-1 and GIP also inhibit apoptosis of primary murine microglia, and upregulate expression of BDNF by primary murine microglia. These results indicate that GLP-1 and GIP affect several critical homeostatic functions of microglia, and could therefore be tested as a novel therapeutic treatment option for brain disorders that are characterized by increased oxidative stress and microglial degeneration. (C) 2017 Elsevier GmbH. All rights reserved.
机译：Incetin激素胰高血糖素样肽（GLP）-1和葡萄糖依赖性胰岛素缺乏多肽（GIP）主要是已知其在周边的代谢功能。 GLP-1和GIP响应于摄入的营养素，肠内分泌细胞分泌。 GLP-1和GIP均刺激胰岛素的胰岛素（3个细胞以及表现出对外周组织的几种生长调节作用的产生和释放。GLP-1和GIP也存在于大脑中，在那里它们提供调制和抗曝光信号对于神经元。然而，关于这些激素对胶质胶质的影响非常有限的信息可以提供大脑的免疫和支持细胞。因此，我们开始解决原发性人小植物和星形胶质细胞，两种胶质细胞亚型，表达GLP-1受体（GLP-1R）和GIP受体（GIPR）分别是检测和响应GLP-1和GIP所必需的。我们进一步测试了这些激素，类似于它们对神经元细胞的影响，具有生长 - 对微胶质细胞的调节，抗氧化和抗凋亡作用。我们展示了原发性人小叶草和星形胶质细胞的GLP-1R和GIPR的第一次表达。我们证明了GLP-1和GIP减少了凋亡死亡尿液BV-2微胶质细胞通过GLP-1R和GIPR的结合和激活，随后的蛋白激酶A（PKA）途径。此外，我们揭示了Incretins上调了脑衍生的神经营养因子（BDNF）的BV-2微胶质增长表达，胶质肌肌肌营养因子（GDNF）和神经生长因子（NGF）中的磷酸肌醇3-激酶（PI3K） - 和MA - 依赖的方式。我们还表明，Incretins通过抑制细胞内反应性氧物质（ROS）的积累和一氧化氮（NO）的释放，以及增加抗氧化糖硫硫氨酸过氧化物酶1（GPX1）的表达，减少BV-2微胶质细胞中的氧化应激。和超氧化物歧化酶1（SOD1）。我们通过证明GLP-1和GIP还抑制原发性鼠髓细胞凋亡的凋亡，并通过初级鼠小胶质细胞上调BDNF的表达。这些结果表明GLP-1和GIP影响微胶质细胞的几个关键稳态功能，因此可以测试作为脑疾病的新疗法治疗选择，其特征在于增加氧化应激和微胶质变性。 （c）2017 Elsevier GmbH。版权所有。

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