Project Summary

Microglia in the CNS parenchyma and macrophages at CNS interfaces act as key sentinel immune cells for
the detection and removal of dying cells and cell debris in the developing, healthy and diseased adult
nervous system. Improper clearance of dead cell material can contribute to the establishment and
progression of neurological disorders. The removal of dead cells (efferocytosis) is best described as a
sequential series of cell biological events divided into “find-me”, “eat-me” and “digest-me” phases. We here
address two largely neglected aspects of dead cell clearance. First, efferocytosis is mostly viewed from the
angle of a single cell. However, clearance of dead cell material in tissues is a population response of many
phagocytes. Based on a novel live-cell-imaging platform, we will define the critical parameters controlling the
population response of efferocytic macrophage and microglia networks. We will have a special focus on how
single cell motility and cytoskeletal regulation influence this population response. Second, phagocytosis of
dead cells fills macrophages and microglia with an additional metabolite load. How this metabolic load is
resolved in macrophages and microglia is largely unknown. By using metabolomics and confocal live cell
imaging techniques, our studies aim at dissecting the metabolic pathways and organelle systems controlling
this metabolic resolution process. We hypothesize that cell motility and metabolic regulation during
efferocytosis are tightly coupled processes that together determine the efferocytic capacity of macrophage
and microglia populations.