Modulation of immune cells and metabolic reprogramming in efferocytosis

Under physiological conditions, cell apoptosis is a silent death process during tissue renewal and remodeling. The phagocytosis of apoptotic cells, known as efferocytosis, is a key process performed primarily by macrophages and dendritic cells, as well as by non-professional phagocytes, such as epithelial cells and fibroblasts. This process, which involves the removal of apoptotic cells, is not just a routine task. It plays a significant role in producing anti-inflammatory mediators that are instrumental in maintaining tissue homeostasis. However, during infection, pathogens can induce different patterns of cell death, including apoptosis. Efferocytosis of infected apoptotic cells is a crucial part of the host defense mechanism. It aids in bacterial clearance, activates the effector functions of phagocytes, and directs the activation of CD4+T lymphocytes. The different stages of the efferocytosis process are not just a sequence of events, but a complex interplay that can interfere with the microenvironment by releasing soluble mediators ("find-me signals") as a rich source of nutrients for phagocytes during the digestion process ("digest-me"), such as amino acids, nucleotides, lipids, and carbohydrates. In recent years, several studies have contributed to unraveling the impact of the different stages of the efferocytosis process on regulating metabolic pathways that support the continuous phagocytosis of apoptotic cells, the activation profile, and the effector functions of phagocytes. In this review, we discuss the impact of efferocytosis on immune cells during homeostasis and infectious diseases, and in the metabolic reprogramming on phagocyte activation. We also explore the role of efferocytosis during the clearance of apoptotic cells in different pathologies.