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

Abstract

The phagocytosis of dead cells by microglia is essential in brain development and homeostasis. However, the mechanism underlying the efficient removal of cell corpses by ramified microglia remains poorly understood. Here, we investigated the phagocytosis of dead cells by ramified microglia in the hippocampal dentate gyrus, where adult neurogenesis and homeostatic cell clearance occur. Two-color imaging of microglia and apoptotic newborn neurons revealed two important characteristics.Firstly, frequent environmental surveillance and rapid engulfment reduced the time required for dead cell clearance. The motile microglial processes frequently contacted and enwrapped apoptotic neurons at the protrusion tips and completely digested them within 3-6 h of the initial contact. Secondly, while a single microglial process engaged in phagocytosis, the remaining processes continued environmental surveillance and initiated the removal of other dead cells. The simultaneous removal of multiple dead cells increases the clearance capacity of a single microglial cell. These two characteristics of ramified microglia contributed to their phagocytic speed and capacity, respectively. Consistently, the cell clearance rate was estimated to be 8-20 dead cells/microglia/day, supporting the efficiency of removing apoptotic newborn neurons. We concluded that ramified microglia specialize in utilizing individual motile processes to detect stochastic cell death events and execute parallel phagocytoses.

Development of a High-Throughput Pipeline to Characterize Microglia Morphological States at a Single-Cell Resolution

“…Cdk1-mediated microtubule remodeling has also recently been shown to be required for efficient cytokine trafficking and release and transformation of microglia from ramified to ameboid forms after LPS exposure in vitro and in situ ( Adrian et al, 2023 ). In contrast, findings from other studies display a reverse relationship, where ramified microglia have been shown to phagocytose synapses during adult neurogenesis ( Sierra et al, 2010 ; Kamei and Okabe, 2023 ), and ameboid microglia show reduced phagocytic capabilities in epilepsy ( Abiega et al, 2016 ; Paolicelli et al, 2022 ). The relationship between form and function is clearly not as dichotomous as historically thought, and there has been an increasing effort in the field to move away from dualistic classification of microglial function and toward a clearer understanding and appreciation of the heterogeneous states of microglia ( Dubbelaar et al, 2018 ; Paolicelli et al, 2022 ).…”

Efferocytosis by macrophages in physiological and pathological conditions: regulatory pathways and molecular mechanisms

“…In the hippocampal dentate gyrus of the central nervous system (CNS), efferocytosis by ramified microglia (phagocytic cells that remove ACs and crops in the brain) balances cell death and neurogenesis to promote homeostasis and brain development, although the underlying mechanism requires further research ( 60 ). Paneth cells are pluripotent cells found in the small intestine.…”

A bottom-up approach identifies the antipsychotic and antineoplastic trifluoperazine and the ribose derivative deoxytubercidin as novel microglial phagocytosis inhibitors

“…During this process, engulfment is tightly controlled by overlapping “find-me”, “eat-me”, and “dońt-eat-me” signals that ensure the fast and specific recognition of the apoptotic cargo (Mehrotra and Ravichandran, 2022). For example, under physiological conditions, they engulf the excess of newborn cells produced in neurogenic niches (Sierra et al, 2010; Diaz-Aparicio et al, 2020) and degrade them in few hours (Kamei and Okabe, 2023). However, in some pathological conditions, the signaling responsible for the coupling between apoptosis and phagocytois is disrupted and phagocytosis efficiency is lost.…”