Dual Pro-Angiogenic and Pro-Fibrotic MARCO⁺ Microglial Phenotype in Diabetic Retinopathy

Area of Science:

• Ophthalmology
• Immunology
• Vascular Biology

Background:

• Proliferative diabetic retinopathy (PDR) involves retinal neovascularization and fibrosis, leading to vision loss.
• Inhibiting vascularization and fibrosis is crucial for managing PDR.
• Fibrovascular membranes (FVMs) in PDR are key sites of pathological changes.

Purpose of the Study:

• To investigate the role of specific microglial subpopulations in PDR.
• To identify potential therapeutic targets for ocular angiogenic and fibrotic diseases.

Main Methods:

• Single-cell sequencing of FVMs from PDR patients.
• In vitro studies using BV2 cells treated with glycated albumin (GA).
• In vivo studies using oxygen-induced retinopathy (OIR) and choroidal neovascularization (CNV) mouse models (WT and MARCO-/-).
• Next-generation sequencing to analyze signaling pathways.
• Pharmacological inhibition of MARCO+ microglia using PolyG.

Main Results:

• A MARCO+ microglial subpopulation with pro-angiogenic and pro-fibrotic effects was identified in PDR FVMs.
• GA upregulated MARCO expression in BV2 cells dose-dependently.
• MARCO+ microglia accumulation enhanced retinal angiogenesis and fibrogenesis in WT mice but not in MARCO-/- mice.
• TLR4/NF-κB signaling pathway activation was linked to increased MARCO+ microglia expression.
• PolyG treatment reduced angiogenesis and fibrogenesis in mouse models.

Conclusions:

• MARCO+ microglia play a significant role in promoting ocular angiogenesis and fibrogenesis.
• Targeting MARCO+ microglia with drugs like PolyG shows therapeutic potential for PDR and similar conditions.
• MARCO+ microglia represent a promising therapeutic target for ocular angiogenic and fibrotic diseases.