Regulatory mechanisms of macrophage programming during dead cell clearance

死细胞清除过程中巨噬细胞编程的调节机制

• 批准号: 496418714
• 负责人: Dr. Maria Tanzer, Ph.D.
• 金额: --
• 依托单位: Abteilung Proteomics and Signal Transduction
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2022
• 资助国家: 德国
• 起止时间: 2021-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/496418714?language=en
• 关键词: Regulatory; mechanisms; macrophage; programming; during

Inflammatory diseases are typically accompanied by increased cell death, which exacerbates inflammation. Dead cells have to be removed to resolve inflammation. Therefore, the body has developed a process termed efferocytosis. With this, macrophages are programmed to recognise and phagocytose apoptotic cells. The efficient removal of dead cells is essential for wound healing and presents a prerequisite to maintain homeostasis. Defects in efferocytosis can lead to auto-immune diseases like rheumatoid arthritis or lupus erythematosus. Regulations of this process in various disease settings are desired, but require profound knowledge. Investigations of efferocytosis using conventional cell biology techniques face difficulties due to its complexity. Firstly, macrophages have to deal with a vast excess of lipids, proteins and metabolites when engulfing dead cells. Secondly, they developed strategies to avoid an inflammatory response when encountering highly inflammatory molecules like nucleic acids. Additionally, efferocytosing macrophages upregulate anti-inflammatory cytokines and undergo significant morphological changes upon engulfment of dead cells. The underlying mechanisms for these processes are still largely unknown. Therefore, we will apply cutting edge proteomic- and genetic approaches to obtain an unprecedented view into critical events that drive efferocytosis and macrophage reprogramming. We will a) characterise dynamically phosphorylated and ubiquitylated proteins and determine functional relevant proteins using genetic screens, b) investigate proteins that undergo organellar translocation and c) identify proteins, which are released during efferocytosis and examine their function in inflammation. Our results will provide insights into the adaptation of macrophages and offer handles to regulate this intricate process and its effect on inflammation.

炎症性疾病通常伴随着增加的细胞死亡，这加剧了炎症。必须去除死细胞以解决炎症。因此，人体已经开发出一种称为肿瘤病的过程。因此，巨噬细胞被编程为识别和吞噬细胞凋亡细胞。有效去除死细胞对于伤口愈合至关重要，并提出了维持体内平衡的先决条件。肾上腺细胞增多症的缺陷会导致类风湿关节炎或红斑狼疮等自身免疫性疾病。需要在各种疾病环境中对此过程进行法规，但需要深刻的知识。使用常规细胞生物学技术对常规细胞增多症的研究由于其复杂性而面临困难。首先，巨噬细胞在吞噬死细胞时必须处理大量过量的脂质，蛋白质和代谢产物。其次，他们制定了遇到高度炎症分子（如核酸）时避免炎症反应的策略。另外，巨噬细胞的遗传细胞会上调抗炎细胞因子，并在死亡细胞吞没后发生显着的形态变化。这些过程的基本机制在很大程度上是未知的。因此，我们将采用最前沿的蛋白质组学和遗传方法，以获得前所未有的观点，以促进伴随着吞噬作用和巨噬细胞重编程的关键事件。我们将a）表征动态磷酸化和泛素化的蛋白质，并使用遗传筛选确定功能相关的蛋白质，b）研究蛋白质的蛋白质，这些蛋白质会经历细胞器的易位，c）鉴定蛋白质，这些蛋白质在经肿瘤中释放并检查其在炎症中的功能。我们的结果将提供对巨噬细胞适应的见解，并提供调节这一复杂过程及其对炎症的影响。