title: Deficiency of ATP-binding cassette transporters A1 and G1 in macrophages increases inflammation and accelerates atherosclerosis in mice.
abstract: BACKGROUND
  Plasma high-density lipoprotein levels are inversely correlated with atherosclerosis. Although it is widely assumed that this is attributable to the ability of high-density lipoprotein to promote cholesterol efflux from macrophage foam cells, direct experimental support for this hypothesis is lacking.
  
  
  OBJECTIVE
  To assess the role of macrophage cholesterol efflux pathways in atherogenesis.
  
  
  RESULTS
  We developed mice with efficient deletion of the ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) in macrophages (MAC-ABC(DKO) mice) but not in hematopoietic stem or progenitor populations. MAC-ABC(DKO) bone marrow (BM) was transplanted into Ldlr(-/-) recipients. On the chow diet, these mice had similar plasma cholesterol and blood monocyte levels but increased atherosclerosis compared with controls. On the Western-type diet, MAC-ABC(DKO) BM-transplanted Ldlr(-/-) mice had disproportionate atherosclerosis, considering they also had lower very low-density lipoprotein/low-density lipoprotein cholesterol levels than controls. ABCA1/G1-deficient macrophages in lesions showed increased inflammatory gene expression. Unexpectedly, Western-type diet-fed MAC-ABC(DKO) BM-transplanted Ldlr(-/-) mice displayed monocytosis and neutrophilia in the absence of hematopoietic stem and multipotential progenitor cells proliferation. Mechanistic studies revealed increased expressions of machrophage colony stimulating factor and granulocyte colony stimulating factor in splenic macrophage foam cells, driving BM monocyte and neutrophil production.
  
  
  CONCLUSIONS
  These studies show that macrophage deficiency of ABCA1/G1 is proatherogenic likely by promoting plaque inflammation and uncover a novel positive feedback loop in which cholesterol-laden splenic macrophages signal BM progenitors to produce monocytes, with suppression by macrophage cholesterol efflux pathways.
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA. mw2537@columbia.edu
authors.forename: Marit
authors.initials: M
authors.lastname: Westerterp
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: Mi
authors.initials: M
authors.lastname: Wang
authors.forename: Tamara A
authors.initials: TA
authors.lastname: Pagler
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Vengrenyuk
authors.forename: Mojdeh S
authors.initials: MS
authors.lastname: Kappus
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Gorman
authors.forename: Prabhakara R
authors.initials: PR
authors.lastname: Nagareddy
authors.forename: Xuewei
authors.initials: X
authors.lastname: Zhu
authors.forename: Sandra
authors.initials: S
authors.lastname: Abramowicz
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
authors.forename: Carrie
authors.initials: C
authors.lastname: Welch
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Laurent
authors.initials: L
authors.lastname: Yvan-Charvet
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D000821:Animal Feed; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002791:Cholesterol, Dietary / Q000378:metabolism; D005487:Foam Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008074:Lipoproteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000473:pathology; D014657:Vasculitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D002791:Cholesterol, Dietary; D008074:Lipoproteins; D011973:Receptors, LDL
keywords: atherosclerosis; high-density lipoprotein; inflammation; macrophages; monocytes