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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Sene
authors.forename: Aslam A
authors.initials: AA
authors.lastname: Khan
authors.forename: Douglas
authors.initials: D
authors.lastname: Cox
authors.forename: Rei E I
authors.initials: RE
authors.lastname: Nakamura
authors.forename: Andrea
authors.initials: A
authors.lastname: Santeford
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Kim
authors.forename: Rohini
authors.initials: R
authors.lastname: Sidhu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Onken
authors.forename: J William
authors.initials: JW
authors.lastname: Harbour
authors.forename: Shira
authors.initials: S
authors.lastname: Hagbi-Levi
authors.forename: Itay
authors.initials: I
authors.lastname: Chowers
authors.forename: Peter A
authors.initials: PA
authors.lastname: Edwards
authors.forename: Angel
authors.initials: A
authors.lastname: Baldan
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.forename: Rajendra S
authors.initials: RS
authors.lastname: Apte
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D002784:Cholesterol / Q000378:metabolism*; D059305:Diet, High-Fat; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008268:Macular Degeneration / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D035683:MicroRNAs / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010641:Phenotype
chemical_list: C577836:ABCA1 protein, human; C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D008074:Lipoproteins; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D002784:Cholesterol
references.citation: J Clin Invest. 2005 Nov;115(11):2979-91
references.pmid: 16239969
references.citation: J Lipid Res. 2011 Jul;52(7):1435-45
references.pmid: 21518695
references.citation: Exp Eye Res. 2005 Dec;81(6):731-41
references.pmid: 16005869
references.citation: Immunity. 2005 Oct;23(4):344-6
references.pmid: 16226499
references.citation: Trends Immunol. 2004 Dec;25(12):677-86
references.pmid: 15530839
references.citation: J Clin Invest. 2007 Nov;117(11):3421-6
references.pmid: 17975672
references.citation: J Biol Chem. 2006 Sep 29;281(39):29401-10
references.pmid: 16887795
references.citation: Science. 2000 Sep 1;289(5484):1524-9
references.pmid: 10968783
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12228-32
references.pmid: 20566875
references.citation: Science. 2010 Jun 18;328(5985):1566-9
references.pmid: 20466882
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7401-6
references.pmid: 20385819
references.citation: Nature. 1996 Oct 24;383(6602):728-31
references.pmid: 8878485
references.citation: Arch Ophthalmol. 1990 Oct;108(10):1442-7
references.pmid: 1699513
references.citation: Am J Ophthalmol. 2004 Mar;137(3):486-95
references.pmid: 15013873
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7395-400
references.pmid: 20385826
references.citation: J Biol Chem. 1996 Jul 26;271(30):17852-60
references.pmid: 8663356
references.citation: Cell Metab. 2005 Feb;1(2):121-31
references.pmid: 16054053
references.citation: Curr Opin Biotechnol. 1999 Dec;10(6):557-63
references.pmid: 10600692
references.citation: Invest Ophthalmol Vis Sci. 2001 Jan;42(1):265-74
references.pmid: 11133878
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):19719-24
references.pmid: 22095132
references.citation: J Lipid Res. 2010 Mar;51(3):451-67
references.pmid: 19797256
references.citation: Nat Immunol. 2006 Apr;7(4):354-9
references.pmid: 16550198
references.citation: J Clin Invest. 2005 May;115(5):1333-42
references.pmid: 15841208
references.citation: J Biol Chem. 2007 Aug 24;282(34):25123-30
references.pmid: 17604270
references.citation: J Lipid Res. 1999 Sep;40(9):1636-46
references.pmid: 10484610
references.citation: Arterioscler Thromb Vasc Biol. 1995 Feb;15(2):276-89
references.pmid: 7749836
references.citation: Biochim Biophys Acta. 2012 Mar;1821(3):386-95
references.pmid: 21824529
references.citation: Science. 2010 Jun 18;328(5985):1570-3
references.pmid: 20466885
references.citation: Cell. 2011 Apr 29;145(3):341-55
references.pmid: 21529710
references.citation: Cell Metab. 2008 May;7(5):365-75
references.pmid: 18460328
references.citation: Prog Retin Eye Res. 2001 Nov;20(6):705-32
references.pmid: 11587915
references.citation: Prog Retin Eye Res. 2009 Nov;28(6):393-422
references.pmid: 19698799
references.citation: J Biol Chem. 2008 Aug 22;283(34):22930-41
references.pmid: 18552351
references.citation: J Clin Invest. 2011 Jul;121(7):2921-31
references.pmid: 21646721
references.citation: Science. 2005 Apr 15;308(5720):421-4
references.pmid: 15761121
references.citation: Immunobiology. 2008;213(9-10):695-9
references.pmid: 18926285
references.citation: J Biol Chem. 2004 Oct 29;279(44):45980-9
references.pmid: 15319426
references.citation: PLoS One. 2010 Apr 23;5(4):e10329
references.pmid: 20428236
references.citation: J Biol Chem. 2001 Oct 19;276(42):38378-87
references.pmid: 11504730
references.citation: Eur J Epidemiol. 2003;18(9):845-54
references.pmid: 14561043
references.citation: Cell Metab. 2005 May;1(5):309-22
references.pmid: 16054078
references.citation: J Leukoc Biol. 2003 Feb;73(2):209-12
references.pmid: 12554797
references.citation: PLoS Med. 2006 Aug;3(8):e310
references.pmid: 16903779