Nitric Oxide Modulates Metabolic Remodeling in Inflammatory Macrophages through TCA Cycle Regulation and Itaconate Accumulation, 2019, Crabtree et al

[Andy]

Highlights

• •
  NO orchestrates metabolic remodeling in macrophages responding to LPS+IFNγ
• •
  NO regulates itaconate metabolism in two models of infection and inflammation
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  NO determines Complex I subunit abundance in inflammatory macrophages
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  Glycolysis is increased in activated NO-deficient cells despite metabolic changes

Summary
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.

Open access at www.cell.com/cell-reports/fulltext/S2211-1247(19)30784-3

 

[Midnattsol]

Interesting. There was one exertion study on CFS-patients where they measured high levels of NO metabolites, although I can't remember seeing this repeated in other studies.

Results: Plasma nitrates differed between the groups, with higher values in the CFS group (F = 6.93, p = 0.003). Nitrate concentration increased in relation to workload and reached higher values in the CFS group, the maximum difference with respect to the control group being 295% (t = 4.88, p < 0.001).

From: https://www.liebertpub.com/doi/10.1089/jwh.2008.1255#B7 Couldn't find it at scihub unfortunately. Also I have no idea if it's eNOS or iNOS.

 

[Wonko]

Does it say anywhere in all those words if more, or less, NO is helpful?

 

[Midnattsol]

That depends what the body uses it for It can regulate different things in the body. In this case it mentions how it can induce a pro-inflammatory state, which would be useful depending if you need the immune system acting up. It's a vasodilator, so it can increase bloodflow to tissues, helpful when there's an increased need for oxygen and/or other nutrients or if the tissue needs to be cleared of some metabolite. If you frequently have low blood-pressure, more vasodilation might make it worse. As it briefly mentions in the summary-section Andy posted, it can also decrease energy production, in the full paper they mention yet another way it can do this.

I probably should wait to post this until my brain is a bit less fogged, but the main idea is it depends. I wouldn't want too much of it for no reason, though.

 

[mariovitali]

This is very interesting , Thank you @Andy

 

[wastwater]

Searched for copaxone,nitric oxide and cytokines for connections.