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

Area of Science:

• Neuroscience
• Immunology
• Ophthalmology

Background:

• The role of infiltrating monocyte-derived macrophages (MDMs) in neurodegeneration is unclear.
• Understanding their precise function and evolution in the degenerating retina is crucial.

Purpose of the Study:

• To track and define the functional evolution of infiltrating monocytes in retinal degeneration models.
• To investigate the pathogenic and homeostatic roles of these cells.
• To identify stage-specific therapeutic targets.

Main Methods:

• Utilized a CCR2-CreER-based lineage-tracing and ablation strategy in mouse models of retinal degeneration.
• Monitored monocyte infiltration, marker acquisition (TMEM119, P2RY12), morphology, and transcriptional changes.
• Assessed the impact of monocyte ablation on neuroinflammation, complement deposition, and photoreceptor survival.

Main Results:

• Infiltrating monocytes downregulate CCR2, acquire microglial markers, and adopt a microglial-like phenotype.
• Early monocyte infiltration exacerbates neuroinflammation by inducing Müller cell C3 production and promoting microglial alternative pathway complement regulation.
• Selective ablation of acute-phase monocytes reduced C3 deposition, suppressed microglial activation, and preserved photoreceptors.

Conclusions:

• Infiltrating monocytes have a dual role: early pathogenic drivers and later contributors to immune homeostasis.
• Monocyte infiltration is a critical, stage-specific therapeutic target for neurodegenerative diseases.
• These findings elucidate the complex interplay between monocytes, microglia, and Müller cells in retinal degeneration.