Article

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: 10.45). 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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    • "Reduction in mitochondrial oxidative phosphorylation is associated with accumulation of mitochondrial TCA intermediates, such as citrate, succinate, and fumarate (Fig. 2) and increased consumption of glutamine and arginine [3,8,12,42–45]. Importantly, this metabolic adaptation is required for pro-inflammatory activation (e.g. in response to LPS) and expression of proper effector function [3–8,33,36–41,46,47]. Intriguingly, the anti-inflammatory cytokine IL-10 limits glycolysis and blocks activation of dendritic cells in response to Toll-like receptor (TLR) activation [41]. "
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    • "GLUT 3 seems to be the predominant transporter expressed by human monocytes, but also expression of GLUT 1 and the insulin-sensitive GLUT 4 is frequently reported (Korgun et al., 2002; Maratou et al., 2007). Activation of immune cells increases GLUT expression and glucose uptake (Krawczyk et al., 2010; Maratou et al., 2007). In dairy cows a single study describes monocyte glucose transporter expression, indicating a postpartal decrease in GLUT 1, 3 and 4 expression on monocytes (O'Boyle et al., 2012). "
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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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