title: IRF2BP2 Reduces Macrophage Inflammation and Susceptibility to Atherosclerosis.
abstract: BACKGROUND
  Inflammation impairs macrophage cholesterol clearance from vascular tissues and promotes atherosclerosis. Inflammatory macrophages suppress expression of the transcription cofactor interferon regulatory factor 2-binding protein 2 (IRF2BP2), and genetic variants near IRF2BP2 associate with ischemic heart disease progression in humans.
  
  
  OBJECTIVE
  To test whether IRF2BP2 in macrophages affects atherosclerosis in mice and humans.
  
  
  RESULTS
  We generated mice that delete IRF2BP2 in macrophages. IRF2BP2-deficient macrophages worsened atherosclerosis in irradiated low-density lipoprotein receptor null-recipient mice and in apolipoprotein E null mice. IRF2BP2-deficient macrophages were inflammatory and had impaired cholesterol efflux because of their inability to activate the cholesterol transporter ABCA1 in response to cholesterol loading. Their expression of the anti-inflammatory transcription factor Krüppel-like factor 2 was markedly reduced. Promoter studies revealed that IRF2BP2 is required for MEF2-dependent activation of Krüppel-like factor 2. Importantly, restoring Krüppel-like factor 2 in IRF2BP2-deficient macrophages attenuated M1 inflammatory and rescued M2 anti-inflammatory gene activation and improved the cholesterol efflux deficit by restoring ABCA1 activation in response to cholesterol loading. In a cohort of 1066 angiographic cases and 1011 controls, homozygous carriers of a deletion polymorphism (rs3045215) in the 3' untranslated region sequence of human IRF2BP2 mRNA had a higher risk of coronary artery disease (recessive model, odds ratio [95% confidence interval]=1.560 [1.179-2.065], P=1.73E-03) and had lower IRF2BP2 (and Krüppel-like factor 2) protein levels in peripheral blood mononuclear cells. The effect of this deletion polymorphism to suppress protein expression was confirmed in luciferase reporter studies.
  
  
  CONCLUSIONS
  Ablation of IRF2BP2 in macrophages worsens atherosclerosis in mice, and a deletion variant that lowers IRF2BP2 expression predisposes to coronary artery disease in humans.
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.). hchen@uottawa.ca astewart@ottawaheart.ca.
authors.forename: Hsiao-Huei
authors.initials: HH
authors.lastname: Chen
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
authors.forename: Kianoosh
authors.initials: K
authors.lastname: Keyhanian
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
authors.forename: Xun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
authors.forename: Ragnar O
authors.initials: RO
authors.lastname: Vilmundarson
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
authors.forename: Naif A M
authors.initials: NA
authors.lastname: Almontashiri
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
authors.forename: Shelly A
authors.initials: SA
authors.lastname: Cruz
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Pandey
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
authors.forename: Nida
authors.initials: N
authors.lastname: Lerma Yap
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
authors.forename: Tiffany
authors.initials: T
authors.lastname: Ho
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
authors.forename: Chloe A
authors.initials: CA
authors.lastname: Stewart
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
authors.forename: Aswin
authors.initials: A
authors.lastname: Hari
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
authors.forename: Michele
authors.initials: M
authors.lastname: Geoffrion
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
authors.forename: Katey J
authors.initials: KJ
authors.lastname: Rayner
authors.affiliation: From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.). hchen@uottawa.ca astewart@ottawaheart.ca.
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
mesh_terms: D020413:3' Untranslated Regions; D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D065840:Protective Factors; D011859:Radiography; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012307:Risk Factors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D002352:Carrier Proteins; D002784:Cholesterol; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D064326:MEF2 Transcription Factors; D009687:Nuclear Proteins; D011973:Receptors, LDL; D014157:Transcription Factors; C577833:Abca1 protein, mouse; C475082:IRF2BP2 protein, human; C000603862:IRF2BP2 protein, mouse; C096161:KLF2 protein, human; C498314:Klf2 protein, mouse
keywords: 3′ untranslated region; atherosclerosis; cholesterol; coronary artery disease; genetics; macrophages