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Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation

Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, USA.
Blood (Impact Factor: 10.43). 03/2010; 115(23):4742-9. DOI: 10.1182/blood-2009-10-249540
Source: PubMed

ABSTRACT Dendritic cells (DCs) are key regulators of innate and acquired immunity. The maturation of DCs is directed by signal transduction events downstream of toll-like receptors (TLRs) and other pattern recognition receptors. Here, we demonstrate that, in mouse DCs, TLR agonists stimulate a profound metabolic transition to aerobic glycolysis, similar to the Warburg metabolism displayed by cancer cells. This metabolic switch depends on the phosphatidyl inositol 3'-kinase/Akt pathway, is antagonized by the adenosine monophosphate (AMP)-activated protein kinase (AMPK), and is required for DC maturation. The metabolic switch induced by DC activation is antagonized by the antiinflammatory cytokine interleukin-10. Our data pinpoint TLR-mediated metabolic conversion as essential for DC maturation and function and reveal it as a potential target for intervention in the control of excessive inflammation and inappropriately regulated immune responses.

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    • "It has been demonstrated that the shift toward aerobic glycolysis induced in DCs by TLR stimulation is driven by the PI3K/Akt pathway. In turn, this process is antagonized by AMPK [17] (Fig. 1). The upregulated aerobic glycolysis insures the energy need of DC activation, and supports the de novo synthesis of fatty acids for the expansion of the endoplasmic reticulum and Golgi for the production and secretion of the effector proteins such as cytokines [21]. "
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    • "can induce HIF-1-dependent metabolic reprogramming toward glycolysis. Toll-like receptor agonists stimulate a metabolic transition to aerobic glycolysis in dendritic cells (DCs) and macrophages, a conversion essential for their maturation and function (Krawczyk et al., 2010; Tannahill et al., 2013). In DCs, nitric oxide is a key player in this switch by acting on components of the mitochondrial ETC to inhibit oxidative phosphorylation. "
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    • "Naïve dendritic cells when activated using TLR ligands or pro-inflamtory cytokines, shift their metabolism from oxidative phosphorylation to aerobic glycolysis (i.e., the Warburg effect). Krawczyk et al. described this phenomenon in DCs and also demonstrated how TLR stimulation is essential for dendritic cell maturation [47]. "
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