@article{25158ae5d8a4470ea64f88fd454e58a9,
title = "Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration",
abstract = "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.",
author = "Abdoulaye Sene and Khan, {Aslam A.} and Douglas Cox and Nakamura, {Rei E.I.} and Andrea Santeford and Kim, {Bryan M.} and Rohini Sidhu and Onken, {Michael D.} and Harbour, {J. William} and Shira Hagbi-Levi and Itay Chowers and Edwards, {Peter A.} and Angel Baldan and Parks, {John S.} and Ory, {Daniel S.} and Apte, {Rajendra S.}",
note = "Funding Information: This work was supported by NIH grant K08EY016139 (R.S.A.); NIH grant R01EY019287 (R.S.A.); NIH Vision Core Grant P30EY02687, U.S. Civilian Research and Development Foundation (R.S.A. and I.C.); NIH grants P01HL049373 (J.S.P.) and R01 HL094525 (J.S.P.); NIH grant R01 HL067773 (D.S.O.); NIH grant HL-107794 (A.B.); NIH grant HL-30568 (P.A.E.); the Carl Marshall Reeves and Mildred Almen Reeves Foundation Inc. Award (R.S.A.); the Research to Prevent Blindness Inc. Career Development Award (R.S.A.); the International Retina Research Foundation (R.S.A.); the American Health Assistance Foundation (R.S.A.); the Lacy Foundation Research Award (A.S.); the Thome Foundation (R.S.A.); and a Research to Prevent Blindness Inc. Unrestricted Grant to Washington University. Mass spectrometry and mouse serum analysis, respectively, were performed in the Metabolomics Facility and the Diabetes Research Center (NIH P60 DK 20579) at Washington University in Saint Louis. The authors would like to acknowledge the insights and constructive input of Drs. Douglas Green, Jayakrishna Ambati, Steve Teitelbaum, Shiming Chen, and Thomas Ferguson regarding these studies. R.S.A. is named as an inventor in a patent application filed by Washington University on the intellectual property presented in this article. ",
year = "2013",
month = apr,
day = "2",
doi = "10.1016/j.cmet.2013.03.009",
language = "English (US)",
volume = "17",
pages = "549--561",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "4",
}