Dual Pro‐Angiogenic and Pro‐Fibrotic <scp>MARCO</scp> ⁺ Microglial Phenotype in Diabetic Retinopathy

Proliferative diabetic retinopathy (PDR) is a complication of diabetic microangiopathy that can cause severe visual impairment. Due to retinal neovascularization and fibrovascular membrane (FVM) formation, inhibition of vascularization and fibrosis plays a key role in PDR. In our study, single-cell sequencing of FVMs from PDR patients identified a MARCO⁺ microglial subpopulation exhibiting both pro-angiogenic and pro-fibrotic effects. In vitro experiments demonstrated that glycated albumin (GA) significantly upregulated MARCO expression in BV2 cells in a dose-dependent manner. In vivo experiments, oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) models were established in wild-type (WT) and MARCO^-/^- mice. The accumulation of MARCO⁺ microglia promoted retinal angiogenesis and fibrogenesis in WT mouse models, but not in MARCO^-/^- mouse models. Mechanistically, next-generation sequencing confirmed that the activation of the TLR4/NF-κB signaling pathway results in the increased expression of MARCO⁺ microglia. Furthermore, the targeted drug PolyG, which inhibits MARCO⁺ microglia, resulted in reduced angiogenesis and fibrogenesis in mouse models. Taken together, we demonstrate that MARCO⁺ microglia could be a potential therapeutic target for ocular angiogenic and fibrotic diseases.