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

Jade D. Bailey, Marina Diotallevi, Thomas Nicol, Eileen McNeill, Andrew Shaw, Surawee Chuaiphichai, Ashley Hale, Anna Starr, Manasi Nandi, Elena Stylianou, Helen McShane, Simon Davis, Roman Fischer, Benedikt M. Kessler, James McCullagh, Keith M. Channon*, Mark J. Crabtree

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

124 Citations (Scopus)

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. Metabolic remodeling underpins inflammatory macrophage activation, but the modulatory mechanisms are still being elucidated. Bailey et al. show that NO regulates specific changes in the abundance of TCA cycle metabolites, itaconate, and catalytic subunits of Complex I in the respiratory chain in inflammatory murine macrophages both in vitro and in vivo.

Original languageEnglish
Pages (from-to)218-230.e7
JournalCell Reports
Volume28
Issue number1
DOIs
Publication statusPublished - 2 Jul 2019

Keywords

  • immunometabolism
  • inflammation
  • macrophage metabolism
  • mitochondria
  • nitric oxide
  • tetrahydrobiopterin

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