Maxed out macs: physiologic cell clearance as a function of macrophage phagocytic capacity

The phagocytic clearance of host cells is important for eliminating dying cells and for the therapeutic clearance of antibody‐targeted cells. As ubiquitous, motile and highly phagocytic immune cells, macrophages are principal players in the phagocytic removal of host cells throughout the body. In recent years, great strides have been made in identifying the molecular mechanisms that control the recognition and phagocytosis of cells by macrophages. However, much less is known about the physical and metabolic constraints that govern the amount of cellular material macrophages can ingest and how these limitations affect the overall efficiency of host cell clearance in health and disease. In this review we will discuss, in the contexts of apoptotic cells and antibody‐targeted malignant cells, how physical and metabolic factors associated with the internalization of host cells are relayed to the phagocytic machinery and how these signals can impact the overall efficiency of cell clearance. We also discuss how this information can be leveraged to increase cell clearance for beneficial therapeutic outcomes. Macrophages play a vital role in the phagocytic clearance of host cells in two important physiologic settings: dead cell clearance (efferocytosis) and therapeutic antibody‐mediated cell clearance. This review discusses the molecular pathways that control how macrophages sense and respond to the mechanophysical and metabolic stress resulting from the engulfment of large numbers of host cells and how these responses can affect the phagocytic capacity of macrophages in physiologic settings.