Polyunsaturated fatty acid balance modulates microglial state in a murine model of oxygen-induced neovascularization

The Oxygen-Induced Retinopathy (OIR) model is a widely used research tool to study pathological retinal neoangiogenesis observed in the development of diseases like retinopathy of prematurity (ROP) and proliferative diabetic retinopathy. While many factors are known to modulate susceptibility to OIR development, less is understood about how nutritional factors such as dietary fatty acids affect disease progression. The retina is enriched in polyunsaturated fatty acids (PUFAs) which are indispensable for normal vision, and recent work has shown that dietary supplementation of ω-6-and ω-3-polyunsaturated fatty acids (PUFAs) can provide a protective role against the pathological neovascularization observed in ROP. In the current study, we interrogated the effects of endogenous ω-3-PUFA enrichment using transgenic fat-1 mice which converts ω-6-PUFAs to ω-3-PUFAs. These animals develop features of ROP but show attenuation in retinopathy development. Using a combination of immunofluorescence and whole retinal RNA sequencing, genes associated with angiogenesis, inflammation, and microglial activation were upregulated in WT OIR vs. WT RA (room air), with little or no change found in fat-1 OIR vs. fat-1 RA. In addition, Fat-1 mice demonstrated differential enrichment of microglial subtypes in response to OIR. This finding suggests that decreased ω-6:ω-3 protects against neovascularization by attenuating hyperoxia-induced microglial activation.