Oxidized phospholipids and phenotypic polarization of macrophages

Oxidized phospholipids (OxPL) were shown to have pro-as well as anti-inflammatory effects, activating a variety of cell types. In particular, we have previously shown that macrophages respond to OxPL by drastically changing their gene expression pattern and function (1). However, it is not known how macrophages adapt their metabolism to changes in tissue oxidation status. We found that macrophages respond to phospholipids containing oxidized fatty acid moieties by reprogramming their metabolism to support either redox homeostasis or inflammatory responses. OxPL-treated macrophages (Mox) adopt a metabolic profile, which is strikingly distinct from M1 and M2 macrophages and characterized by accumulation of antioxidant metabolites involved in glutathione synthesis. The metabolic adaptation in Mox macrophages coincided with Hif1α-and Nrf2-dependent gene expression. On the other hand, OxPL suppressed mitochondrial respiration by a mechanism involving TLR2-dependent ceramide production. Treatment of macrophages with truncated OxPL suppressed mitochondrial respiration and promoted expression of genes controlling redox homeostasis, while non-fragmented oxygenated OxPL induced pro-inflammatory gene expression, without inhibiting bioenergetics. Using a targeted lipidomics approach, we demonstrate that both truncated and oxygenated OxPL species were abundant in healthy, lean adipose tissue. Accordingly, we identify a prominent population of previously unrecognized CX3CR1 - F4/80 lo CD11b + cells in lean adipose tissue, which are also positive for HO1 + and Txnrd1 + , resembling the Mox phenotype. These cells are characterized by a quiescent bioenergetic profile, which can be mimicked by macrophages polarized with truncated OxPL. Surprisingly, we found that high-fat diet feeding led to a disproportional increase of oxygenated unfragmented OxPL species. In obese adipose tissue, the predominant macrophage population was CX3CR1 + F4/80 hi CD11b + positive, expressing both CD11c + and CD206 + and characterized by a highly energetic metabolism. Our findings demonstrate that macrophages respond to OxPL and adapt their metabolism to control redox homeostasis. The data suggest that by sensing OxPL, macrophages translate tissue oxidation status into antioxidant and inflammatory responses via modulation of metabolism and bioenergetics.