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代谢来响应促炎刺激与抗炎刺激（巨噬细胞极化）。反过来，中间代谢物调节细胞内信号传导和基因表达。因此，乙酰辅酶A除了通过驱动柠檬酸循环产生能量外，还是蛋白质和组蛋白乙酰化的底物。 ATP 柠檬酸裂解酶 (ACLY) 是一种负责胞质乙酰辅酶 A 生成的酶，通过组蛋白乙酰化支持基因表达，以响应癌细胞和脂肪细胞中营养水平的变化，以及小鼠巨噬细胞中的细胞因子 IL-4。我们的初步数据显示，IL-4 刺激的花生四烯酸 15-脂氧合酶 (ALOX15) 表达对 ACLY 抑制敏感。然而，ACLY 和乙酰辅酶 A 对 IL-4 诱导的人巨噬细胞极化的影响仍不清楚。此外，我们之前已经表明，AMP 依赖性蛋白激酶 (AMPK) 介导的 IL-4 刺激的巨噬细胞中 ALOX15 表达的抑制可能部分是通过改变组蛋白乙酰化而发生的。在本提案中，我们旨在阐明 ACLY 驱动的乙酰辅酶 A 生成对人巨噬细胞响应 IL-4 极化的影响。我们假设 ACLY 通过与染色质上的基因调控元件物理关联，可以局部调节 IL-4 响应基因子集上的组蛋白乙酰化。其次，我们揭示了依赖于 ACLY 驱动的乙酰辅酶 A 的蛋白质乙酰化模式的改变。这将在蛋白质组筛选中得到解决。第三，我们研究了 AMPK 对蛋白质乙酰化的影响。我们认为 AMPK 抑制 ACLY 的活性，从而引起组蛋白乙酰化的变化，从而引起基因表达的变化。我们的研究进一步了解了新陈代谢，特别是乙酰辅酶A的生成如何与巨噬细胞极化相关。