Bioenergetic programming of macrophages by the apolipoprotein A-I mimetic peptide 4F.
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.
*Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
Geeta
G
Datta
‡Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
Philip A
PA
Kramer
‡Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
Michelle S
MS
Johnson
‡Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
Hirotaka
H
Sawada
*Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
Lesley E
LE
Smythies
§Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
David K
DK
Crossman
†Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
Balu
B
Chacko
†Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
Scott W
SW
Ballinger
‡Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
David G
DG
Westbrook
*Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
Palgunachari
P
Mayakonda
*Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
G M
GM
Anantharamaiah
†Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
Victor M
VM
Darley-Usmar
*Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
C Roger
CR
White
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D040761:Biomimetic Materials / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D010455:Peptides / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D016632:Apolipoprotein A-I; D001549:Benzamides; D005227:Fatty Acids; D047495:PPAR gamma; D010455:Peptides; D011725:Pyridines; C458508:T 0070907; C582295:apolipoprotein A-I mimetic peptide 4F