title: Iron gene expression profile in atherogenic Mox macrophages.
abstract: The role of macrophage iron in the physiopathology of atherosclerosis is an open question that needs to be clarified. In atherosclerotic lesions, recruited macrophages are submitted to cytokines and oxidized lipids which influence their phenotype. An important phenotypic population driven by oxidized phospholipids is the Mox macrophages which present unique biological properties but their iron phenotype is not well described.
  
  
  
  To investigate the effect of Mox polarization by oxidized LDL (oxLDL) on macrophage iron metabolism in the absence or presence of proinflammatory stimuli.
  
  
  
  Bone marrow-derived macrophages were treated with different sources of LDL and/or LPS/IFNγ (M1 activator). Expression of ferroportin (Slc40a1, alias Fpn), heme oxygenase-1 (Hmox1), H- and L-ferritin (Fth1 and Ftl1), hepcidin (Hamp), ceruloplasmin (Cp) and interleukine-6 (Il6) was followed by quantitative PCR. FPN and HMOX1 protein expression was analyzed by immunofluorescence and in-cell-Western blotting.
  
  
  
  Mox macrophages expressed increased Hmox1 and Fth1 levels with basal FPN protein levels despite the significant increase of Fpn mRNA. Upregulation of Hmox1 and Fpn mRNA was specific to LDL oxidative modification and mediated by NRF2. The downregulation of both Cp isoforms and the upregulation of Hamp expression observed in Mox macrophages suggest that FPN mediated iron export could be compromised. Simultaneous exposure to oxLDL and LPS/IFNγ leads to a mixed Mox/M1 phenotype that is closer to M1.
  
  
  
  A microenvironment rich in oxLDL and proinflammatory cytokines could promote macrophage iron retention and lipid accumulation profiles, a specific cell phenotype that likely contributes to lesion development and plaque instability in atherosclerosis.
authors.affiliation: INSERM UMR 1043, CNRS UMR 5282, Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France; Departamento da Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal; University of Lisboa, Faculty of Sciences, BioISI - Biosystems & Integrative Sciences Institute, Campo Grande, Lisboa, Portugal.
authors.forename: Liliana
authors.initials: L
authors.lastname: Marques
authors.affiliation: INSERM UMR 1048 I2MC, Université de Toulouse, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Negre-Salvayre
authors.affiliation: Departamento da Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal; University of Lisboa, Faculty of Sciences, BioISI - Biosystems & Integrative Sciences Institute, Campo Grande, Lisboa, Portugal. Electronic address: luciana.costa@insa.min-saude.pt.
authors.forename: Luciana
authors.initials: L
authors.lastname: Costa
authors.affiliation: INSERM UMR 1043, CNRS UMR 5282, Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France; IRSD, Université de Toulouse, INSERM, INRA, INP-ENVT, Université de Toulouse 3 Paul Sabatier, Toulouse, France. Electronic address: francois.canonne-hergaux@inserm.fr.
authors.forename: François
authors.initials: F
authors.lastname: Canonne-Hergaux
mesh_terms: D000107:Acetylation; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics; D002478:Cells, Cultured; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics; D008810:Mice, Inbred C57BL; D059467:Transcriptome; D015854:Up-Regulation; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D000098742:Ferroportin; C099252:oxidized low density lipoprotein; D007501:Iron; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: Atherosclerosis; Iron metabolism; Macrophage; Mox; Oxidized LDL; Proinflammatory stimuli