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

衰老的特征是慢性炎症过程。巨噬细胞作为先天免疫细胞对这种永久性炎症有明显的促进作用。我们自己的数据显示，GILZ(糖皮质激素诱导的亮氨酸拉链)蛋白调节从幼鼠获得的小鼠巨噬细胞的激活：GILZ水平的急剧下降放大了巨噬细胞的防御准备。另一方面，GILZ水平的增加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，这伴随着免疫反应的提高。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会在这些组织中引起表观遗传学变化。表观遗传学变化越来越被认为是衰老过程的重要特征。基于这一知识，本项目将检验以下假设：(I)慢性年龄相关性炎症反应是基于GILZ水平降低。减弱的GILZ会损害炎症的消退，这通常是由于耐受现象引起的。(Ii)GILZ水平随年龄的下降是由糖皮质激素代谢改变引起的。(Iii)巨噬细胞本身显示出衰老的迹象，并促进它们所在组织的衰老现象。这些假说将在组织培养、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衰老。该项目将提供关于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.