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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
Cell reports | 2019

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.

Pubmed ID: 31269442

Associated grants

  • Agency: British Heart Foundation, United Kingdom
    Id: RG/12/5/29576
  • Agency: British Heart Foundation, United Kingdom
    Id: FS/14/56/31049
  • Agency: Wellcome Trust, United Kingdom
    Id: 206331/Z/17/Z
  • Agency: British Heart Foundation, United Kingdom
    Id: RG/17/10/32859
  • Agency: Wellcome Trust, United Kingdom
    Id: 090532/Z/09/Z
  • Agency: British Heart Foundation, United Kingdom
    Id: RG/07/003/23133
  • Agency: British Heart Foundation, United Kingdom
    Id: RE/18/3/34214
  • Agency: British Heart Foundation, United Kingdom
    Id: RE/13/1/30181

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