Journal
CELL REPORTS
Volume 28, Issue 1, Pages 218-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.06.018
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Funding
- British Heart Foundation [FS/14/56/31049]
- British Heart Foundation Programme [RG/17/10/32859, RG/12/5/29576]
- NIH Research (NIHR) Oxford Biomedical Research Centre
- BHF Centre of Research Excellence, Oxford [RE/13/1/30181, RE/18/3/34214]
- Wellcome Trust [090532/Z/09/Z]
- BBSRC [BB/R013829/1] Funding Source: UKRI
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Classical activation of macrophages (M(LPS+IFN gamma)) 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 tetrahy-drobiopterin (BH4) modulates IL-1 beta 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.
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