Metabolic reprogramming of macrophages upon activation with a NOD1 receptor agonist

• Nina E. Murugina
• Balyasova L.S.
• Anna S. Budikhina
• Polina V. Maksimchik
• Dagil Yu.A.
• Vladimir V. Murugin
• Chkadua G.Z.
• Boris V. Pinegin
• Mikhail V. Pashenkov

Abstract

Activation of immune system cells is accompanied by a profound rearrangement of their metabolism, or metabolic reprogramming. Muramyl peptides, which are fragments of bacterial peptidoglycan, activatie innate immune cells through NOD1 and/or NOD2 receptors. Here, we characterize, for the first time, alterations of carbohydrate and energy metabolism of human macrophages activated by a NOD1 agonist, N-acetyl-D-muramyl-L-alanyl-D-isoglutamyl-meso-diaminopimelic acid (M-triDAP) in comparison with a TLR4 agonist, lipopolysaccharide (LPS). Real-time analysis of cell metabolism showed that both agonists, within 1 h after addition to cells, boosted glycolysis along with a minor reduction of oxygen consumption.

The effect of either agonist on glycolysis was blocked by an Akt kinase inhibitor, but was independent of the mTORC1 kinase complex and elevation of glycolytic enzyme expression. Unlike LPS, M-triDAP caused almost no induction of aconitate decarboxylase 1, an enzyme breaking the Krebs’ cycle. The effect of 2-deoxyglucose (a competitive inhibitor of glycolysis) and Akt inhibitor on M-triDAP-induced cytokine expression was ambiguous. The Akt inhibitor reduced TNF, IL-6 and IL-1β, expression, whereas 2-DG inhibited TNF and IL-6 expression at an early stage (1 h), but enhanced it at a late stage (4-9 h) after addition of M-triDAP. Mechanisms whereby these inhibitors affect cytokine expression are discussed.

Keywords:imacrophages; metabolic reprogramming; glycolysis; muramyl peptides; NOD1

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