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PMID: 20651288 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2.

Circulation research ·Vol. 107 ·No. 6 ·2010-09-17 ·Pages 737-46

Kadl A, Meher AK, Sharma PR, Lee MY, Doran AC, Johnstone SR, Elliott MR, Gruber F, Han J, Chen W, Kensler T, Ravichandran KS, Isakson BE, Wamhoff BR, Leitinger N

Abstract

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. To examine macrophage phenotypic changes in response to oxidized phospholipids that are present in atherosclerotic lesions. 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. 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.

MeSH Terms
Animals Atherosclerosis/genetics,metabolism Cells, Cultured Female Immunophenotyping Macrophages/classification,physiology Mice Mice, Inbred C57BL Mice, Knockout NF-E2-Related Factor 2/biosynthesis,deficiency,genetics,physiology Oxidation-Reduction Phospholipids/metabolism,physiology
Chemicals
NF-E2-Related Factor 2 Nfe2l2 protein, mouse Phospholipids
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Kadl Alexandra
Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
Meher Akshaya K
Sharma Poonam R
Lee Monica Y
Doran Amanda C
Johnstone Scott R
Elliott Michael R
Gruber Florian
Han Jenny
Chen Wenshu
Kensler Thomas
Ravichandran Kodi S
Isakson Brant E
Wamhoff Brian R
Leitinger Norbert
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Article Info
Journal
Circulation research
Abbr.
Circ Res
ISSN
1524-4571
DOI
10.1161/CIRCRESAHA.109.215715
Published
2010-09-17
Epub
2010-00-22
Pages
737-46
Language
English
Region
United States
NLM ID
0047103
PMCID
PMC2941538
Subset
IM
Grants
NHLBI NIH HHS · R01-HL-084422-01 · United States
NHLBI NIH HHS · R01 HL084422-01 · United States
NIDDK NIH HHS · P30 DK067629 · United States
NHLBI NIH HHS · R01 HL084422-02 · United States
NHLBI NIH HHS · R01 HL084422-03 · United States
NHLBI NIH HHS · R01 HL084422-05 · United States
NHLBI NIH HHS · R01 HL084422-04 · United States
NIAID NIH HHS · T32 AI055432 · United States
NHLBI NIH HHS · R01 HL084422 · United States
External Links
PubMed source DOI: 10.1161/CIRCRESAHA.109.215715 PMC Full Text View journal details
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