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细胞死亡的增加，这会加剧炎症。必须去除死亡细胞来化解炎症。因此，身体发展了一种称为胞吐作用的过程。有了这一点，巨噬细胞被编程来识别和吞噬凋亡的细胞。有效地清除死亡细胞是伤口愈合的关键，也是维持体内平衡的先决条件。胞吐缺陷可导致自身免疫性疾病，如类风湿性关节炎或红斑狼疮。在各种疾病环境中对这一过程的监管是可取的，但需要深厚的知识。由于其复杂性，使用传统细胞生物学技术研究泡腾作用面临困难。首先，巨噬细胞吞噬死亡细胞时，必须处理大量过剩的脂类、蛋白质和代谢物。其次，当遇到像核酸这样的高度炎性分子时，他们制定了避免炎症反应的策略。此外，吞噬细胞泡泡的巨噬细胞可上调抗炎细胞因子，并在吞噬死亡细胞时发生显著的形态变化。这些过程的基本机制在很大程度上仍不清楚。因此，我们将应用尖端的蛋白质组学和遗传学方法，以前所未有的视角看待驱动泡泡细胞吞噬和巨噬细胞重新编程的关键事件。我们将a)鉴定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)研究经历细胞器易位的蛋白质，c)识别在胞吐过程中释放的蛋白质，并检测它们在炎症中的功能。我们的结果将为巨噬细胞的适应提供洞察力，并为调节这一复杂的过程及其对炎症的影响提供处理。