Regulation of IL-4-induced human macrophage polarization by acetyl-CoA and AMP-activated protein kinase

乙酰辅酶 A 和 AMP 激活蛋白激酶对 IL-4 诱导的人巨噬细胞极化的调节

基本信息

批准号：
260847914
负责人：
Privatdozent Dr. Dmitry Namgaladze
金额：
--
依托单位：
Institut für Biochemie I: Pathobiochemie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/260847914?language=en
关键词：
Regulation IL induced human macrophage

项目摘要

Macrophages respond to pro- versus anti-inflammatory stimuli (macrophage polarization) by altering their metabolism. In turn, intermediate metabolites regulate intracellular signaling and gene expression. Thus, acetyl-CoA, besides its role in energy generation by driving the citrate cycle, is a substrate for protein and histone acetylation. ATP citrate lyase (ACLY), an enzyme responsible for cytosolic acetyl-CoA generation, support gene expression through histone acetylation in responses to altered nutrient levels in cancer cells and adipocytes, but also to the cytokine IL-4 in murine macrophages. Our preliminary data show an IL-4-stimulated expression of arachidonate 15-lipoxygenase (ALOX15) to be sensitive to ACLY inhibition. However, the impact of ACLY and acetyl-CoA on IL-4-induced human macrophage polarization remains unclear. Furthermore, we have previously shown that AMP-dependent protein kinase (AMPK) - mediated inhibition of ALOX15 expression in IL-4-stimulated macrophages may partly occur through altered histone acetylation. In this proposal we aim to elucidate the influence of ACLY-driven acetyl-CoA generation on human macrophage polarization in response to IL-4. We postulate that ACLY, by physically associating with gene regulatory elements on chromatin, may locally regulate histone acetylation on a subset of IL-4-responsive genes. Second we reveal an altered pattern of protein acetylation, dependent on ACLY-driven acetyl-CoA. This will be address in a proteomic screen. Third, we investigate the influence of AMPK on protein acetylation. We suggest that AMPK inhibits the activity of ACLY, thereby eliciting changes of histone acetylation and thus, gene expression. Our study adds to understand how metabolism and, in particular, acetyl-CoA generation, connects to macrophage polarization.

巨噬细胞通过改变其新陈代谢来对促疾病与抗炎刺激（巨噬细胞极化）作出反应。反过来，中间代谢物调节细胞内信号传导和基因表达。因此，除了通过驱动柠檬酸盐循环在能量产生中的作用外，乙酰辅酶A是蛋白质和组蛋白乙酰化的底物。 ATP柠檬酸裂解酸酯（ACLY）是一种负责胞质乙酰辅酶A产生的酶，通过组蛋白乙酰化支持癌细胞和脂肪细胞中营养水平改变的反应，以及对鼠巨噬细胞中细胞因子IL-4的反应。我们的初步数据表明，蛛网膜酸15-脂氧合酶（ALOX15）的IL-4刺激表达对ACLY抑制很敏感。然而，Acly和乙酰-COA对IL-4诱导的人类巨噬细胞极化的影响尚不清楚。此外，我们先前已经表明，AMP依赖性蛋白激酶（AMPK） - 在IL-4刺激的巨噬细胞中介导的ALOX15表达抑制可能部分通过改变组蛋白乙酰化而发生。在此提案中，我们旨在阐明辅助驱动的乙酰辅酶A产生对IL-4响应人类巨噬细胞极化的影响。我们假设Acly通过与染色质上的基因调节元素进行物理关联，可以在IL-4反应基因的子集上局部调节组蛋白乙酰化。其次，我们揭示了蛋白质乙酰化的改变模式，取决于粘液驱动的乙酰辅酶A。这将是在蛋白质组学屏幕中的地址。第三，我们研究了AMPK对蛋白质乙酰化的影响。我们建议AMPK抑制ACLY的活性，从而引起组蛋白乙酰化的变化，从而引起基因表达。我们的研究增加了新陈代谢，尤其是乙酰-COA产生如何与巨噬细胞极化相关。