Infiltrating monocytes augment alternative complement activation and exacerbate inherited retinal degeneration in a...

Area of Science:

• Neuroscience
• Immunology
• Ophthalmology

Background:

• Microglia and macrophages accumulate in retinal degenerative diseases, influencing progression.
• Distinct roles of these immune cells in retinal degeneration are not fully understood.

Purpose of the Study:

• To define the fate and function of infiltrating monocyte-derived macrophages (MDM) in retinal degeneration.
• To investigate the impact of these cells on disease progression and explore therapeutic potential.

Main Methods:

• Generated a CCR2-CreER mouse line on the rd10 background for monocyte tracking and ablation.
• Utilized immunohistochemistry and transcriptomic profiling to analyze cell behavior and gene expression.
• Performed selective ablation of infiltrating monocytes to assess functional outcomes.

Main Results:

• Infiltrating monocytes acquired microglia-like characteristics (TMEM119+, P2RY12+) and were partially cleared by resident microglia.
• Microglia-monocyte interactions promoted Müller cell C3 production and alternative complement pathway activation.
• Selective monocyte ablation reduced microglial activation, inflammation, complement deposition, and ameliorated photoreceptor degeneration.

Conclusions:

• Infiltrating monocytes are key drivers of immune dysregulation and inflammation in retinal degeneration.
• Targeting infiltrating monocytes shows therapeutic potential for neuroprotection in retinal degenerative diseases.