Depletion of endomembrane reservoirs drives phagocytic appetite exhaustion in macrophages

During phagocytosis, F-actin and local membrane secretion grows a phagocytic cup around a bound particle ultimately entrapping the particle within a phagosome. The phagosome then fuses with endosomes and lysosomes to digest the particle. After particle degradation, phagosomes fragment to reform lysosomes and maintain phagocyte degradative capacity. As finite systems, phagocytes have a maximal phagocytic capacity, which should blunt further phagocytosis. However, the processes responsible for appetite exhaustion are not known. We found that macrophages at capacity retained Fcγ receptors levels and did not shrink in size. Instead, surface membrane in-folding, membrane tension, and cortical F-actin were reduced in exhausted macrophages. Moreover, exhausted macrophages were depleted for both endosomes and lysosomes, and consequently, focal endosome exocytosis in remaining externally bound particles was blunted. In comparison, if phagosome resolution was permitted macrophages regained the phagocytic appetite. Altogether, we propose that depletion of the endomembrane pools is a major determinant of phagocytic fatigue as macrophages reach their phagocytic capacity, though other processes are also at play.