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 persist and integrate into the retinal macrophage niche, restoring myeloid homeostatic distribution 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 secondary photoreceptor injury by inflammation. These findings reveal a temporal transition in monocyte fate and function, from acute contributors to neuroinflammatory pathology to persistent components of a remodeled retinal myeloid compartment, and identify disease stage as a critical consideration for therapies targeting monocyte recruitment. Homeostasis: In the healthy retina, resident microglia maintain a surveillance state, characterized by ramified morphology and an evenly tiled distribution. Acute Pathology: During acute injury, infiltrating monocytes trigger a pathogenic cascade: they cause microglia clustering and phagocytosis, induce Müller glia to produce complement C3, and reprogram microglia to downregulate the inhibitor CFH, leading to unchecked complement activation and photoreceptor death. Chronic Resolution: In the chronic stable phase, surviving monocyte-derived macrophages (MDMs) integrate with resident microglia-derived macrophages (MiDMs), acquiring a microglia-like phenotype to establish a new, stable myeloid homeostatic distribution.