Sex differences on laser-induced choroidal neovascularization and short-chain fatty acid treatment in a mouse model

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, with a clinical presentation that varies between sexes. In late-stage AMD, choroidal neovascularization (CNV) triggers retinal inflammation and degeneration, processes that are exacerbated by an overactive response of retinal microglial cells. Short-chain fatty acids (SCFAs) have emerged as potential treatments for AMD due to their anti-inflammatory properties. In this study, we investigate the effects of SCFA treatment in a laser-induced CNV mouse model, focusing on sex-dependent differences in disease progression and microglial response. Our findings demonstrate distinct sex-specific patterns in the development of CNV and associated pathological hallmarks. SCFA treatment resulted in a slight increase in density of Iba1⁺ microglial cells in females at 3 days post-laser (3dpl), while it prevented an increase in males at 7 dpl, with both sexes showing enhanced microglial ramification. The dynamics of microglial density were likely linked to protective effects on CNV lesion, leakage size, and inflammation, which occurred earlier in females and later in males. At transcriptional level, SCFA showed mixed effects, mainly targeting inflammation resolution, mitochondrial support, and neuronal repair in a sex-dependent manner. In vitro, SCFAs reduced microglial phagocytosis of retinal debris, suggesting a potential anti-inflammatory action. This study underscores the importance of considering sex-specific responses in the development of AMD treatments, such as SCFAs, and highlights the need for personalized therapeutic strategies.