Regulatory mechanisms of macrophage programming during dead cell clearance

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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.