Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation.
Complex interplay between T helper (Th) cells and macrophages contributes to the formation and progression of atherosclerotic plaques. While Th1 cytokines promote inflammatory activation of lesion macrophages, Th2 cytokines attenuate macrophage-mediated inflammation and enhance their repair functions. In spite of its biologic importance, the biochemical and molecular basis of how Th2 cytokines promote maturation of anti-inflammatory macrophages is not understood. We show here that in response to interleukin-4 (IL-4), signal transducer and activator of transcription 6 (STAT6) and PPARgamma-coactivator-1beta (PGC-1beta) induce macrophage programs for fatty acid oxidation and mitochondrial biogenesis. Transgenic expression of PGC-1beta primes macrophages for alternative activation and strongly inhibits proinflammatory cytokine production, whereas inhibition of oxidative metabolism or RNAi-mediated knockdown of PGC-1beta attenuates this immune response. These data elucidate a molecular pathway that directly links mitochondrial oxidative metabolism to the anti-inflammatory program of macrophage activation, suggesting a potential role for metabolic therapies in treating atherogenic inflammation.
Vats
Divya
D
Division of Endocrinology, Metabolism and Gerontology, Department of Medicine and Graduate Program in Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
Mukundan
Lata
L
Odegaard
Justin I
JI
Zhang
Lina
L
Smith
Kristi L
KL
Morel
Christine R
CR
Wagner
Roger A
RA
Greaves
David R
DR
Murray
Peter J
PJ
Chawla
Ajay
A
D000818:Animals; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D025461:Feedback, Physiological / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors
D005227:Fatty Acids; D008070:Lipopolysaccharides; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D015847:Interleukin-4; D007371:Interferon-gamma; D005947:Glucose