Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration

Abdoulaye Sene, Aslam A. Khan, Douglas Cox, Rei E.I. Nakamura, Andrea Santeford, Bryan M. Kim, Rohini Sidhu, Michael D. Onken, J. William Harbour, Shira Hagbi-Levi, Itay Chowers, Peter A. Edwards, Angel Baldan, John S. Parks, Daniel S. Ory, Rajendra S. Apte

Research output: Contribution to journalArticle

116 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)549-561
Number of pages13
JournalCell Metabolism
Volume17
Issue number4
DOIs
StatePublished - Apr 2 2013
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Sene, A., Khan, A. A., Cox, D., Nakamura, R. E. I., Santeford, A., Kim, B. M., Sidhu, R., Onken, M. D., Harbour, J. W., Hagbi-Levi, S., Chowers, I., Edwards, P. A., Baldan, A., Parks, J. S., Ory, D. S., & Apte, R. S. (2013). Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration. Cell Metabolism, 17(4), 549-561. https://doi.org/10.1016/j.cmet.2013.03.009