A role for the centrosome in regulating the rate of neuronal efferocytosis by microglia in vivo

Abstract

During brain development, many newborn neurons undergo apoptosis and are engulfed by microglia, the tissue-resident phagocytes of the brain, in a process known as efferocytosis. A hallmark of microglia is their highly branched morphology characterized by the presence of numerous dynamic extensions that these cells use for scanning the brain parenchyma and engulfing unwanted material. The mechanisms driving branch formation and apoptotic cell engulfment in microglia are unclear. By taking a live-imaging approach in zebrafish, we show that while microglia generate multiple microtubule-based branches, they only successfully engulf one apoptotic neuron at a time. Further investigation into the mechanism underlying this sequential engulfment revealed that targeted migration of the centrosome into one branch is predictive of phagosome formation and polarized vesicular trafficking. Moreover, experimentally doubling centrosomal numbers in microglia increases the rate of engulfment and even allows microglia to remove two neurons simultaneously, providing direct supporting evidence for a model where centrosomal migration is a rate-limiting step in branch-mediated efferocytosis. Conversely, light-mediated depolymerization of microtubules causes microglia to lose their typical branched morphology and switch to an alternative mode of engulfment, characterized by directed migration towards target neurons, revealing unexpected plasticity in their phagocytic ability. Finally, building on work focusing on the establishment of the immunological synapse, we identified a conserved signalling pathway underlying centrosomal movement in engulfing microglia.

In vivo imaging of the phagocytic dynamics underlying efficient clearance of adult‐born hippocampal granule cells by ramified microglia

“…However, the mechanism underlying this retrograde movement has not been clarified. In the zebrafish optic tectum, apoptotic neurons are removed by microglial phagocytosis, which is initiated by forming phagocytic cups without translocation of the cell body, similar to the phagocytic behavior of ramified microglia observed in the mouse SGZ (Möller et al, 2022). The experimental perturbation of the microtubule system disrupted the pattern of phagocytosis in zebrafish microglia.…”

Extra centrosomes induce PIDD1‐mediated inflammation and immunosurveillance

“…A new role of centrosomes to tune innate immunity toward infection is currently emerging (Moller et al , 2022; Weier et al , 2022). Recent studies have also expanded our view identifying the centrosome as a signaling hub able to facilitate the formation of NLRP3‐ and Pyrin‐inflammasome (Magupalli et al , 2020; Yang et al , 2020).…”

Understanding the diversity and dynamics of in vivo efferocytosis: Insights from the fly embryo

“…Morphologically, they are highly spiky cells, closely resembling the microglia, which are the resident macrophages of the vertebrate CNS. 122,123 Furthermore, like the microglia, the Drosophila phagocytic glia appear to use their spiky, "filopodial" protrusions to reach out and grasp cellular debris (Figure 2). 78 While embryonic glial phagocytosis appears to be morphologically homogeneous, engulfment throughout embryogenesis can be far more diverse, as exhibited by the very dynamic and multifunctional macrophages.…”