Characterization of Macroph-aging: the Role of GILZ (Glucocortioid-Induced Leucin Zipper)

衰老以慢性炎症过程为特征。巨噬细胞作为先天免疫细胞明显有助于这种永久性炎症。我们自己的数据表明，蛋白GILZ（糖皮质激素诱导亮氨酸拉链）调节小鼠巨噬细胞的激活，从幼鼠获得：GILZ水平的急性下降放大了巨噬细胞的防御准备。另一方面，增加GILZ水平有助于炎症的消退和静息状态的重建。在老年动物的免疫细胞中，我们观察到GILZ水平下降，这与免疫反应升高有关。同时，我们可以证明炎症过程以及巨噬细胞的存在或不存在诱导这些组织的表观遗传变化。表观遗传变化越来越被认为是衰老过程的重要特征。基于这些知识，本项目将测试以下假设：(I)慢性年龄依赖性炎症反应是基于降低的GILZ水平。减薄的GILZ损害炎症的消退，这通常是由于耐受性现象。（II） GILZ水平的年龄依赖性下降是由糖皮质激素代谢改变引起的。（三）巨噬细胞本身表现出衰老的迹象，并在其所处的组织中促进衰老现象。这些假设将在组织培养、小鼠体内研究以及人类肺巨噬细胞实验中得到验证。该项目首次旨在通过下一代测序技术破译小鼠和人类巨噬细胞的表观遗传老化。该项目将提供巨噬细胞衰老现象的基础知识，以及这些现象如何促进整个生物体的衰老过程。

Aging is characterized by chronic inflammatory processes. Macrophages as innate immune cells distinctly contribute to this permanent inflammation. Our own data show that the protein GILZ (glucocorticoid-induced leucine zipper) regulates the activation of mouse macrophages obtained from young mice: an acute decrease in GILZ levels amplifies the defense readiness of macrophages. On the other hand, increasing GILZ levels contribute to the resolution of inflammation and to the re-establishment of a resting state.In immune cells from aged animals we observed decreased GILZ levels, which go along with an elevated immune response. At the same time we could show that inflammatory processes as well as the presence or absence of macrophages induce epigenetic changes in these tissues. Epigenetic changes have increasingly been recognized as important characteristics of aging processes.Based on this knowledge the following hypotheses will be tested within this project:(I) Chronic age-dependent inflammatory reactions are based on reduced GILZ levels. Attenuated GILZ impairs the resolution of inflammation, which are normally due to tolerization phenomena.(II) The age-dependent decrease of GILZ levels is induced by an altered glucocorticoid metabolism.(III) Macrophages themselves show signs of senescence and promote aging phenomena in the tissues, in which they reside. The hypotheses will be tested in tissue cultures, in mouse in vivo investigations, as well as in experiments on human lung macrophages. For the first time this project aims to decipher the epigenetic aging of macrophages from mice and humans via next generation sequencing techniques.The project will deliver fundamental knowledge on aging phenoma in macrophages and how these contribute to aging processes of the whole organism.