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

ABSTRACT 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.