Specific microglial subtypes and inflammatory mechanisms in early diabetic retinopathy

In diabetic retinopathy (DR), a blinding disease, retinal microglia-induced inflammatory responses precede microangiopathy. However, the mechanism by which microglia participate in the development of DR in a high-glucose microenvironment remains unclear. Surprisingly, in this study, we discovered two disease-specific rat retinal microglial subtypes with different proinflammatory characteristics that were closely related to the onset and progression of inflammation in DR using single-cell RNA sequencing. We also revealed different activation orders, mutual activation regulation mechanisms and dynamic changes in polarization phenotypes between these subtypes. Furthermore, we constructed an inflammatory network involving microglia, blood-derived macrophages and other retinal nonneuronal cells. Our comprehensive analysis further elucidates the pathogenesis of DR; redefines the classification criteria of microglia; and provides mechanistic insights for redefining the diagnosis, staging, and anti-inflammatory treatment of early DR.