title: Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways.
abstract: BACKGROUND
  A crucial step in atherogenesis is the infiltration of the subendothelial space of large arteries by monocytes where they differentiate into macrophages and transform into lipid-loaded foam cells. Macrophages are heterogeneous cells that adapt their response to environmental cytokines. Th1 cytokines promote monocyte differentiation into M1 macrophages, whereas Th2 cytokines trigger an "alternative" M2 phenotype.
  
  
  OBJECTIVE
  We previously reported the presence of CD68(+) mannose receptor (MR)(+) M2 macrophages in human atherosclerotic plaques. However, the function of these plaque CD68(+)MR(+) macrophages is still unknown.
  
  
  RESULTS
  Histological analysis revealed that CD68(+)MR(+) macrophages locate far from the lipid core of the plaque and contain smaller lipid droplets compared to CD68(+)MR(-) macrophages. Interleukin (IL)-4-polarized CD68(+)MR(+) macrophages display a reduced capacity to handle and efflux cellular cholesterol because of low expression levels of the nuclear receptor liver x receptor (LXR)α and its target genes, ABCA1 and apolipoprotein E, attributable to the high 15-lipoxygenase activity in CD68(+)MR(+) macrophages. By contrast, CD68(+)MR(+) macrophages highly express opsonins and receptors involved in phagocytosis, resulting in high phagocytic activity. In M2 macrophages, peroxisome proliferator-activated receptor (PPAR)γ activation enhances the phagocytic but not the cholesterol trafficking pathways.
  
  
  CONCLUSIONS
  These data identify a distinct macrophage subpopulation with a low susceptibility to become foam cells but high phagocytic activity resulting from different regulatory activities of the PPARγ-LXRα pathways.
authors.affiliation: Univ Lille Nord de France, Lille, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Chinetti-Gbaguidi
authors.forename: Morgane
authors.initials: M
authors.lastname: Baron
authors.forename: Mohamed Amine
authors.initials: MA
authors.lastname: Bouhlel
authors.forename: Jonathan
authors.initials: J
authors.lastname: Vanhoutte
authors.forename: Corinne
authors.initials: C
authors.lastname: Copin
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Sebti
authors.forename: Bruno
authors.initials: B
authors.lastname: Derudas
authors.forename: Thérèse
authors.initials: T
authors.lastname: Mayi
authors.forename: Gael
authors.initials: G
authors.lastname: Bories
authors.forename: Anne
authors.initials: A
authors.lastname: Tailleux
authors.forename: Stephane
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
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D057093:Orphan Nuclear Receptors / Q000378:metabolism* / Q000502:physiology; D047495:PPAR gamma / Q000378:metabolism*; D010587:Phagocytosis / Q000502:physiology*; D058226:Plaque, Atherosclerotic / Q000378:metabolism* / Q000473:pathology
chemical_list: D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D002784:Cholesterol