Dual Pro-Angiogenic and Pro-Fibrotic MARCO 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.