Regulatory mechanisms of macrophage programming during dead cell clearance

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，身体已经开发了一个过程称为红细胞增多症。有了这个，巨噬细胞被编程为识别和吞噬凋亡细胞。有效去除死细胞对于伤口愈合至关重要，并且是维持体内平衡的先决条件。红细胞增多症的缺陷会导致自身免疫性疾病，如类风湿性关节炎或红斑狼疮。这一过程在各种疾病环境中的调节是期望的，但需要深刻的知识。由于其复杂性，使用常规细胞生物学技术对红细胞增多症进行调查面临困难。首先，巨噬细胞在吞噬死细胞时必须处理大量过量的脂质、蛋白质和代谢物。其次，他们开发了在遇到高度炎症分子如核酸时避免炎症反应的策略。此外，吞噬巨噬细胞上调抗炎细胞因子，并在吞噬死细胞后发生显著的形态学变化。这些过程的基本机制在很大程度上仍然是未知的。因此，我们将应用最先进的蛋白质组学和遗传学方法，以获得前所未有的观点，进入驱动巨噬细胞和巨噬细胞重编程的关键事件。我们将a）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，以及c）鉴定在胞浆细胞增多期间释放的蛋白质，并检查它们在炎症中的功能。我们的研究结果将为巨噬细胞的适应性提供见解，并提供控制这一复杂过程及其对炎症的影响的方法。

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.