An innate immunity signaling process suppresses macrophage ABCA1 expression through IRAK-1-mediated downregulation of retinoic acid receptor alpha and NFATc2.
ATP-binding cassette transporter A1 (ABCA1) plays a central role in promoting cholesterol efflux from macrophages, thereby reducing the risk of foam cell formation and atherosclerosis. The expression of ABCA1 is induced by members of the nuclear receptor family of transcription factors, including retinoic acid receptors (RARs). A key innate immunity signaling kinase, IRAK-1, has been associated with an increased risk of atherosclerosis in humans and mice. This prompted us to investigate the potential connection between IRAK-1 and the expression of ABCA1. Here, we demonstrate that nuclear RARalpha levels are dramatically elevated in IRAK-1(-/-) macrophages. Correspondingly, IRAK-1(-/-) macrophages exhibit increased expression of ABCA1 mRNA and protein, as well as elevated cholesterol efflux in response to the RAR ligand ATRA. Analysis of the ABCA1 proximal promoter revealed binding sites for both RAR and NFAT. Chromatin immunoprecipitation assays demonstrated increased binding of RARalpha and NFATc2 to the ABCA1 promoter in IRAK-1(-/-) macrophages compared to wild-type macrophages. Additionally, lipopolysaccharide pretreatment reduced the nuclear levels of RARalpha and decreased ABCA1 expression and cholesterol efflux in wild-type but not in IRAK-1(-/-) cells. In summary, this study reveals a novel connection between innate immunity signaling processes and the regulation of ABCA1 expression in macrophages and defines a potential therapeutic target for treating atherosclerosis.
Maitra
Urmila
U
Department of Biology, Virginia Tech, Blacksburg, VA 24061, USA.
Parks
John S
JS
Li
Liwu
L
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D014212:Tretinoin / Q000494:pharmacology
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008070:Lipopolysaccharides; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; C000607071:RARA protein, human; D012333:RNA, Messenger; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D016572:Cyclosporine; D002784:Cholesterol; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse