Nitric Oxide Modulates Metabolic Remodeling in Inflammatory Macrophages through TCA Cycle Regulation and Itaconate Accumulation

Cell Rep. 2019 Jul 2;28(1):218-230.e7. doi: 10.1016/j.celrep.2019.06.018.

Abstract

Classical activation of macrophages (M(LPS+IFNγ)) elicits the expression of inducible nitric oxide synthase (iNOS), generating large amounts of NO and inhibiting mitochondrial respiration. Upregulation of glycolysis and a disrupted tricarboxylic acid (TCA) cycle underpin this switch to a pro-inflammatory phenotype. We show that the NOS cofactor tetrahydrobiopterin (BH4) modulates IL-1β production and key aspects of metabolic remodeling in activated murine macrophages via NO production. Using two complementary genetic models, we reveal that NO modulates levels of the essential TCA cycle metabolites citrate and succinate, as well as the inflammatory mediator itaconate. Furthermore, NO regulates macrophage respiratory function via changes in the abundance of critical N-module subunits in Complex I. However, NO-deficient cells can still upregulate glycolysis despite changes in the abundance of glycolytic intermediates and proteins involved in glucose metabolism. Our findings reveal a fundamental role for iNOS-derived NO in regulating metabolic remodeling and cytokine production in the pro-inflammatory macrophage.

Keywords: immunometabolism; inflammation; macrophage metabolism; mitochondria; nitric oxide; tetrahydrobiopterin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopterins / analogs & derivatives
  • Biopterins / metabolism
  • Citric Acid Cycle* / drug effects
  • Electron Transport / drug effects
  • Endotoxemia / chemically induced
  • Endotoxemia / metabolism
  • GTP Cyclohydrolase / genetics
  • GTP Cyclohydrolase / metabolism
  • Glycolysis / drug effects
  • Inflammation / metabolism*
  • Interferon-gamma / pharmacology
  • Interleukin-1beta / metabolism
  • Isocitrate Dehydrogenase / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophage Activation / drug effects
  • Macrophages / drug effects
  • Macrophages / enzymology
  • Macrophages / metabolism*
  • Mice
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Mycobacterium Infections / metabolism
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Peptide Fragments / metabolism
  • Proteome / genetics
  • Proteome / metabolism
  • Succinates / metabolism*
  • Succinic Acid / metabolism
  • Tandem Mass Spectrometry

Substances

  • Interleukin-1beta
  • Lipopolysaccharides
  • Peptide Fragments
  • Proteome
  • Succinates
  • interleukin-1beta (163-171)
  • Biopterins
  • Nitric Oxide
  • Interferon-gamma
  • Succinic Acid
  • Isocitrate Dehydrogenase
  • Idh1 protein, mouse
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • GTP Cyclohydrolase
  • sapropterin
  • itaconic acid