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Nitric oxide modulates metabolic remodelling and immunometabolism in inflammatory murine macrophages

ABSTRACT: Classical stimulation of macrophages (MLPS/IFNγ) elicits the expression of inducible nitric oxide synthase (iNOS), generating large amounts of nitric oxide (NO) and inhibiting respiration. Consequent upregulation of glycolysis and a disrupted tricarboxylic acid (TCA) cycle underpin this switch to a pro-inflammatory phenotype. Here we show that the NOS cofactor tetrahydrobiopterin (BH4) modulates key aspects of metabolic remodelling in activated bone-marrow-derived macrophages (BMDMs) via NO production. Using two complementary mouse models that each lack the capacity for inducible NO generation, through different mechanisms, we reveal that NO regulates macrophage respiratory function via changes in the abundance of critical N-module subunits in Complex I, by HIF1α-mediated glycolytic remodelling, and by modulating levels of the critical TCA cycle metabolites, and inflammatory mediators, citrate, succinate, and itaconate. Taken together, our findings reveal new critical roles for iNOS-derived NO that are required for metabolic remodelling and cytokine production in macrophage inflammatory responses.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Bone Marrow-derived Macrophage, Macrophage

SUBMITTER: Simon Davis

LAB HEAD: Roman Fischer

PROVIDER: PXD010628 | Pride | 2019-05-31

REPOSITORIES: Pride

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			Action	DRS
	FL0698_MSQ0982_Jade_151117_A-2.msf	Msf
	FL0698_MSQ0982_Jade_151117_A-2.pepxml	Pepxml
	FL0698_MSQ0982_Jade_151117_A1_20171201193552.raw	Raw
	FL0698_MSQ0982_Jade_151117_A2.raw	Raw
	FL0698_MSQ0982_Jade_151117_A3.raw	Raw

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