Impaired Cholesterol Efflux in Senescent Macrophages Promotes Age-Related Macular Degeneration

Abstract

Summary Pathologic angiogenesis mediated by abnormally polarized macrophages plays a central role in common age-associated diseases such as atherosclerosis, cancer and macular degeneration. Here we demonstrate that abnormal polarization in older macrophages is caused by programmatic changes that lead to reduced expression of ATP binding cassette transporter ABCA1. Downregulation of ABCA1 by microRNA-33 impairs the ability of macrophages to effectively efflux intracellular cholesterol, which in turn leads to higher levels of free cholesterol within senescent macrophages. Elevated intracellular lipid polarizes older macrophages to an abnormal, alternatively activated phenotype that promotes pathologic vascular proliferation. Mice deficient for Abca1, but not Abcg1, demonstrate an accelerated aging phenotype, whereas restoration of cholesterol efflux using LXR agonists or miR-33 inhibitors reverses it. Monocytes from older humans with age-related macular degeneration showed similar changes. These findings provide an avenue for therapeutic modulation of macrophage function in common age-related diseases.

Pathways of cholesterol homeostasis in mouse retina responsive to dietary and pharmacologic treatments

“…These were eight direct LXR targets ( Srebp-1c , Srebp-1a , Idol , Abca1 , Abcg1 , apoE , apoD , and Scd1 ) and three indirect targets regulated via SREBP-1c ( Fasn , Acc1 , and Acc2 ). Only two of these genes ( Abca1 and Abcg1 ) were shown to be responsive to TO9 previously ( 62,63 ). When combined, the data on gene responsiveness to dietary and pharmacologic treatments enable two conclusions.…”

mTOR Enhances Foam Cell Formation by Suppressing the Autophagy Pathway

“…Aggressive lowering of lipid deposition obviously reduces atherosclerotic coronary lesion, suggesting a new approach to prevent atherosclerotic complications (Glass, 2002;Arai et al, 2010). Autophagic pathway is related with cholesterol efflux from macrophages, a process relevant to atherosclerosis (Ouimet and Marcel, 2012;Sene et al, 2013). Increasing evidence suggests that mTOR is a critical negative regulator for autophagy (Ravikumar et al, 2004;Jung et al, 2010).…”

GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients

“…Laser-capture microdissection was performed as described previously (33). Briefly, eyeballs were embedded in OCT compound (Sakura Finetek) and immediately flash frozen on dry ice.…”