Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation

Cell Metab. 2006 Jul;4(1):13-24. doi: 10.1016/j.cmet.2006.05.011.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Energy Metabolism / physiology*
  • Fatty Acids / metabolism
  • Feedback, Physiological / physiology
  • Glucose / metabolism
  • Inflammation / metabolism*
  • Interferon-gamma / pharmacology
  • Interleukin-4 / pharmacology
  • Lipopolysaccharides / pharmacology
  • Macrophage Activation
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Mice
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Models, Biological
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • STAT6 Transcription Factor / metabolism
  • Trans-Activators / drug effects
  • Trans-Activators / metabolism*
  • Transcription Factors

Substances

  • Fatty Acids
  • Lipopolysaccharides
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Interleukin-4
  • Interferon-gamma
  • Glucose

Associated data

  • GEO/GSE5003