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Published on: April 3, 2017
Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2
Alexandra Kadl1, Akshaya K Meher, Poonam R Sharma
1Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
Rationale:
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.
Methods And 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.
Insights
Researchers identified a new macrophage phenotype, termed Mox, which arises from oxidized phospholipids. This Mox phenotype, regulated by Nrf2, has reduced function and is prevalent in atherosclerosis, impacting chronic inflammation.
Area of Science:
- Immunology
- Molecular Biology
- Cardiovascular Research
Background:
- Macrophages exhibit diverse phenotypes influenced by their microenvironment.
- Atherosclerosis involves oxidative damage and chronic inflammation, but macrophage responses to oxidized molecules remain unclear.
Purpose of the Study:
- To investigate macrophage phenotypic alterations induced by oxidized phospholipids found in atherosclerotic lesions.
Main Methods:
- Murine macrophages were treated with oxidized phospholipids.
- Gene expression analysis (whole-genome arrays) and gene ontology clustering were performed.
- Nrf2 knockout (Nrf2(-/-)) and low-density lipoprotein receptor knockout (LDLR(-/-)) mouse models were utilized.
Main Results:
- Oxidized phospholipids induced a novel macrophage phenotype (Mox) with distinct gene expression, reduced phagocytosis, and chemotaxis compared to M1/M2 phenotypes.
- The Mox phenotype is characterized by Nrf2-mediated redox-regulatory gene expression.
- Mox macrophages constitute a significant portion (30%) of macrophages in advanced atherosclerotic lesions of LDLR(-/-) mice.
Conclusions:
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is identified as a key regulator in the formation of the Mox macrophage phenotype.
- The unique characteristics of Mox macrophages suggest a significant role in atherosclerotic lesion progression and other chronic inflammatory conditions.
