Bioenergetic programming of macrophages by the apolipoprotein A-I mimetic peptide 4F

• Published in: Biochemical journal Vol. 467; no. 3; p. 517
• Main Authors: Datta, Geeta, Kramer, Philip A, Johnson, Michelle S, Sawada, Hirotaka, Smythies, Lesley E, Crossman, David K, Chacko, Balu, Ballinger, Scott W, Westbrook, David G, Mayakonda, Palgunachari, Anantharamaiah, G M, Darley-Usmar, Victor M, White, C Roger
• Format: Journal Article
• Language: English
• Published: England 01.05.2015
• Subjects: Anti-Inflammatory Agents - pharmacology; Apolipoprotein A-I - metabolism; Benzamides - pharmacology; Biomimetic Materials - pharmacology; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cells, Cultured; Energy Metabolism; Fatty Acids - metabolism; Gene Expression Regulation - drug effects; Humans; Lipid Metabolism - drug effects; Lipid Metabolism - genetics; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mitochondria - drug effects; Mitochondria - metabolism; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; Oxygen Consumption; Peptides - pharmacology; PPAR gamma - antagonists & inhibitors; Pyridines - pharmacology
• ISSN: 1470-8728
• DOI: 10.1042/BJ20131635

The apoA-I (apolipoprotein A-I) mimetic peptide 4F favours the differentiation of human monocytes to an alternatively activated M2 phenotype. The goal of the present study was to test whether the 4F-mediated differentiation of MDMs (monocyte-derived macrophages) requires the induction of an oxidative metabolic programme. 4F treatment induced several genes in MDMs that play an important role in lipid metabolism, including PPARγ (peroxisome-proliferator-activated receptor γ) and CD36. Addition of 4F was associated with a significant increase in FA (fatty acid) uptake and oxidation compared with vehicle treatment. Mitochondrial respiration was assessed by measurement of the OCR (oxygen-consumption rate). 4F increased basal and ATP-linked OCR as well as maximal uncoupled mitochondrial respiration. These changes were associated with a significant increase in ΔΨm (mitochondrial membrane potential). The increase in metabolic activity in 4F-treated MDMs was attenuated by etomoxir, an inhibitor of mitochondrial FA uptake. Finally, addition of the PPARγ antagonist T0070907 to 4F-treated MDMs reduced the expression of CD163 and CD36, cell-surface markers for M2 macrophages, and reduced basal and ATP-linked OCR. These results support our hypothesis that the 4F-mediated differentiation of MDMs to an anti-inflammatory phenotype is due, in part, to an increase in FA uptake and mitochondrial oxidative metabolism.