Microglia engagement and clearance of dying neurons is regulated by CX3CR1

Abstract

Neuronal cell death is a hallmark of many neurodegenerative diseases. Effective detection and clearance of cell debris is essential to prevent a degenerative cascade. Brain-resident microglia perform these functions through complex cell-cell signaling involving both “find-me” and “eat-me” cues; however, the precise in vivo mechanisms governing microglial responses to neuronal death remain incompletely understood. To examine microglial responses to tissue damage and neuronal cell death in vivo, we investigated neuron/microglia CX3CR1 signaling in mouse neocortex using intravital optical imaging combined with 2Phatal, a single-cell ablation technique that models individual neuron programmed cell death. Disruption of CX3CR1 signaling via Cx3cr1 knockout altered chemotactic responses to focal tissue damage selectively in non-inflammatory contexts. Furthermore, Cx3cr1 knockout led to delayed cell corpse clearance under both low and high neuronal death conditions, partly due to a delay in microglial engagement with dying cells. These findings uncover a precise, context-specific role for CX3CR1 signaling in regulating microglial engagement and phagocytic clearance of dying neocortical neurons in vivo, with implications for understanding microglial dysfunction in neurodegenerative disease.

The authors' abstract, as published at the source. Journal of Neuroinflammation, 2026 · DOI ↗