Project 461647

Macrophages are a diverse group of immune cells that play a major role in eliminating dangerous particles like bacteria, pollutants, and even tumour and dead cells. Macrophages do this by recognizing, binding to, and then engulfing these particles - this is called phagocytosis. Engulfed particles are enclosed within compartments called phagosomes. Phagosomes then transform into a degradative organelle by fusing with lysosomes, which deliver acid and degradative enzymes. As a result, particles are digested and then phagosomes fragment in a process called phagosome resolution to recycle membranes. We have good understanding of how phagocytosis and phagosome maturation occurs. We also know that macrophages can engulf many particulates - for example, a macrophage can engulf 60 E. coli on average - but there is a limit to how many particles can be eaten. Macrophages that reach this limit stop eating. Yet, we do not know how macrophages determine when they should stop engulfing. Moreover, we also know that given enough time, macrophages recover their phagocytic appetite. But once again, we do not know how macrophages recover their appetite. These questions have no answer, but this is important as it speaks to the ability of macrophages to continuously engulf and clear dangerous particles and to maintain their usefulness over their lifetime. We will test if changes to phagocytic receptors, activation of inhibitory signals, the state of membrane resources, and biophysical processes like membrane tension help instruct macrophages when to stop and when to recover their appetite. Importantly, we will test if macrophages that recover their appetite are better adapted and can eat even more particles. Overall, this is pioneering work on phagocytic exhaustion and recovery since there is very little known about these processes. This could then lead to new therapeutics that harness macrophage phagocytosis to treat infectious diseases, tumours, and inflammation.