title: Liver X receptor activation stimulates iron export in human alternative macrophages.
abstract: BACKGROUND
  In atherosclerotic plaques, iron preferentially accumulates in macrophages where it can exert pro-oxidant activities.
  
  
  OBJECTIVE
  The objective of this study was, first, to better characterize the iron distribution and metabolism in macrophage subpopulations in human atherosclerotic plaques and, second, to determine whether iron homeostasis is under the control of nuclear receptors, such as the liver X receptors (LXRs).
  
  
  RESULTS
  Here we report that iron depots accumulate in human atherosclerotic plaque areas enriched in CD68 and mannose receptor (MR)-positive (CD68(+)MR(+)) alternative M2 macrophages. In vitro IL-4 polarization of human monocytes into M2 macrophages also resulted in a gene expression profile and phenotype favoring iron accumulation. However, M2 macrophages on iron exposure acquire a phenotype favoring iron release, through a strong increase in ferroportin expression, illustrated by a more avid oxidation of extracellular low-density lipoprotein by iron-loaded M2 macrophages. In line, in human atherosclerotic plaques, CD68(+)MR(+) macrophages accumulate oxidized lipids, which activate LXRα and LXRβ, resulting in the induction of ABCA1, ABCG1, and apolipoprotein E expression. Moreover, in iron-loaded M2 macrophages, LXR activation induces nuclear factor erythroid 2-like 2 expression, thereby increasing ferroportin expression, which, together with a decrease of hepcidin mRNA levels, promotes iron export.
  
  
  CONCLUSIONS
  These data identify a role for M2 macrophages in iron handling, a process regulated by LXR activation.
authors.affiliation: From Université Lille 2, Lille, France (G.B., S.C., J.V., B.D., C.C., M.F., M.D., L.B., C.Z., B.J., B.S., G.C.-G.); Inserm U1011, Lille, France (G.B., S.C., J.V., B.D., C.C., M.F., M.D., L.B., B.S., G.C.-G.); Institut Pasteur de Lille, France (G.B., S.C., J.V., B.D., C.C., M.F., M.D., L.B., B.S., G.C.-G.); European Genomic Institute for Diabetes, Lille, France (G.B., S.C., J.V., B.D., C.C., M.F., M.D., L.B., B.S., G.C.-G.); and Centre Hospitalier Régional Universitaire de Lille, France (S.H., C.Z., B.J.).
authors.forename: Gaël
authors.initials: G
authors.lastname: Bories
authors.forename: Sophie
authors.initials: S
authors.lastname: Colin
authors.forename: Jonathan
authors.initials: J
authors.lastname: Vanhoutte
authors.forename: Bruno
authors.initials: B
authors.lastname: Derudas
authors.forename: Corinne
authors.initials: C
authors.lastname: Copin
authors.forename: Mélanie
authors.initials: M
authors.lastname: Fanchon
authors.forename: Mehdi
authors.initials: M
authors.lastname: Daoudi
authors.forename: Loïc
authors.initials: L
authors.lastname: Belloy
authors.forename: Stephan
authors.initials: S
authors.lastname: Haulon
authors.forename: Christophe
authors.initials: C
authors.lastname: Zawadzki
authors.forename: Brigitte
authors.initials: B
authors.lastname: Jude
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Giulia
authors.initials: G
authors.lastname: Chinetti-Gbaguidi
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D002478:Cells, Cultured; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000502:physiology*; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000378:metabolism* / Q000473:pathology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001057:Apolipoproteins E; D007501:Iron; D037181:Lectins, C-Type; D000071518:Liver X Receptors; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D057093:Orphan Nuclear Receptors; D011956:Receptors, Cell Surface; C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C000605213:NR1H3 protein, human
keywords: atherosclerosis; iron; macrophages; receptors, cytoplasmic and nuclear
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