Dysregulation of Macrophage Cholesterol Homeostasis in AMD Pathogenesis

Abstract

Purpose: In addition to aging, recent genetic studies have demonstrated that the regulation of innate immunity and lipid metabolism is strongly associated with AMD pathogenesis. In macrophages, cholesterol efflux is mediated by the ABCA1 and ABCG1 transporters. We investigated the effect of chronic dysregulation of macrophage cholesterol homeostasis on drusen biogenesis and AMD complications.

Methods: We performed an extensive analysis of key features of AMD in ABCA1/G1-deficient mice and their wild type littermates. Mice 2 to 24 months of age were sequentially examined for fundus appearance, ocular morphology and retinal function. In addition, we explored fundus angiography, visual acuity and contrast sensitivity in ABCA1/G1 deficient mice and their age-matched controls. We also analyzed the impact of selective depletion of these transporters in macrophage cholesterol homeostasis and its regulatory function.

Results: We found that targeted depletion of ABCA1 transformed macrophages into disease promoting cells as evidenced by the increased pathological angiogenesis observed in ABCA1 cKO mice in the laser-induced CNV model. In addition, analysis of human PBMC isolated from young individuals (age range 25-34 years) or old (age range 67-87 years) donors diagnosed with neovascular AMD revealed that ABCA1 expression was significantly reduced in old donors. In old macrophages, downregulation of ABCA1 by miR-33 was associated with an accumulation of excess free cholesterol. Enhancing cholesterol efflux in senescent macrophages restored their functional capacity to regulate pathological angiogenesis.

Conclusions: These data suggest that alteration of macrophage cholesterol efflux may contribute to drusen biogenesis and potentially to AMD pathogenesis.

Keywords: 412 age-related macular degeneration • 557 inflammation • 583 lipids