title: Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2.
abstract: BACKGROUND
  Macrophages change their phenotype and biological functions depending on the microenvironment. In atherosclerosis, oxidative tissue damage accompanies chronic inflammation; however, macrophage phenotypic changes in response to oxidatively modified molecules are not known.
  
  
  OBJECTIVE
  To examine macrophage phenotypic changes in response to oxidized phospholipids that are present in atherosclerotic lesions.
  
  
  RESULTS
  We show that oxidized phospholipid-treated murine macrophages develop into a novel phenotype (Mox) that is strikingly different from the conventional M1 and M2 macrophage phenotypes. Compared to M1 and M2, Mox macrophages show a different gene expression pattern, as well as decreased phagocytotic and chemotactic capacity. Treatment with oxidized phospholipids induces both M1 and M2 macrophages to switch to the Mox phenotype. Whole-genome expression array analysis and subsequent gene ontology clustering revealed that the Mox phenotype was characterized by abundant overrepresentation of Nrf2-mediated expression of redox-regulatory genes. In macrophages isolated from Nrf2(-/-) mice, oxidized phospholipid-induced gene expression and regulation of redox status were compromised. Moreover, we found that Mox macrophages comprise 30% of all macrophages in advanced atherosclerotic lesions of low-density lipoprotein receptor knockout (LDLR(-/-)) mice.
  
  
  CONCLUSIONS
  Together, we identify Nrf2 as a key regulator in the formation of a novel macrophage phenotype (Mox) that develops in response to oxidative tissue damage. The unique biological properties of Mox macrophages suggest this phenotype may play an important role in atherosclerotic lesion development as well as in other settings of chronic inflammation.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kadl
authors.forename: Akshaya K
authors.initials: AK
authors.lastname: Meher
authors.forename: Poonam R
authors.initials: PR
authors.lastname: Sharma
authors.forename: Monica Y
authors.initials: MY
authors.lastname: Lee
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Doran
authors.forename: Scott R
authors.initials: SR
authors.lastname: Johnstone
authors.forename: Michael R
authors.initials: MR
authors.lastname: Elliott
authors.forename: Florian
authors.initials: F
authors.lastname: Gruber
authors.forename: Jenny
authors.initials: J
authors.lastname: Han
authors.forename: Wenshu
authors.initials: W
authors.lastname: Chen
authors.forename: Thomas
authors.initials: T
authors.lastname: Kensler
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
authors.forename: Brant E
authors.initials: BE
authors.lastname: Isakson
authors.forename: Brian R
authors.initials: BR
authors.lastname: Wamhoff
authors.forename: Norbert
authors.initials: N
authors.lastname: Leitinger
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D016130:Immunophenotyping; D008264:Macrophages / Q000145:classification / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism / Q000502:physiology*
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010743:Phospholipids