Journal
CELL METABOLISM
Volume 17, Issue 4, Pages 549-561Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2013.03.009
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Funding
- NIH [K08EY016139, R01EY019287, P30EY02687, P01HL049373, R01 HL094525, R01 HL067773, HL-107794, HL-30568]
- U.S. Civilian Research and Development Foundation
- Carl Marshall Reeves and Mildred Almen Reeves Foundation Inc.
- Research to Prevent Blindness Inc.
- International Retina Research Foundation
- American Health Assistance Foundation
- Lacy Foundation
- Thome Foundation
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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.
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