Infiltrating Monocyte Fate Switch in Retinal Degeneration: From Early Pathology to Late Homeostasis

The contribution of infiltrating monocyte-derived macrophages (MDMs) to neurodegeneration remains poorly understood. Using a CCR2-CreER–based lineage-tracing and ablation strategy in mouse models of retinal degeneration, we precisely tracked infiltrating monocytes and defined their functional evolution. We found that monocytes entering the degenerating retina rapidly downregulate CCR2 and progressively acquire microglial markers (e.g., TMEM119, P2RY12), adopt a ramified morphology, and acquire a transcriptional signature highly analogous to that of resident microglia-derived macrophages (MiDMs). While a subset of monocytes is cleared by activated microglia during the acute phase, others persist and integrate into the retinal macrophage niche, restoring myeloid homeostasis in later stages. Functionally, early monocyte infiltration is pathogenic; it amplifies neuroinflammation by inducing Müller cells to produce complement C3 and shifts microglial complement regulation toward the alternative pathway. Critically, selective ablation of monocytes during this acute phase attenuated C3 deposition, suppressed microglial activation, and preserved photoreceptors. Together, these findings reveal a temporally bifurcated role for infiltrating monocytes—as early drivers of complement-mediated pathology and later contributors to immune homeostasis—and identify monocyte infiltration as a stage-specific therapeutic target in neurodegenerative disease.