Cell Metabolism
Volume 17, Issue 4, 2 April 2013, Pages 549-561
Journal home page for Cell Metabolism

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

https://doi.org/10.1016/j.cmet.2013.03.009Get rights and content
Under an Elsevier user license
open archive

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.

Highlights

► Macrophage senescence impairs cholesterol efflux and promotes macular degeneration ► Senescent macrophages polarize to a proangiogenic, disease-promoting phenotype ► Macrophage cholesterol efflux is regulated by miR33 and its target ABCA1 ► Age-related decrease in macrophage cholesterol efflux is therapeutically reversible

Cited by (0)

8

These authors contributed equally to this work