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

• Published in: Blood Vol. 115; no. 23; pp. 4742 - 4749
• Main Authors: Krawczyk, Connie M., Holowka, Thomas, Sun, Jie, Blagih, Julianna, Amiel, Eyal, DeBerardinis, Ralph J., Cross, Justin R., Jung, Euihye, Thompson, Craig B., Jones, Russell G., Pearce, Edward J.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 10.06.2010; Americain Society of Hematology; American Society of Hematology
• Series: Immunobiology
• Subjects: Animals; Biological and medical sciences; Dendritic Cells - immunology; Dendritic Cells - metabolism; Glycolysis - genetics; Glycolysis - immunology; Hematologic and hematopoietic diseases; Immunobiology; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Interleukin-10 - genetics; Interleukin-10 - immunology; Interleukin-10 - metabolism; Medical sciences; Mice; Mice, Knockout; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - immunology; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - immunology; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - immunology; Toll-Like Receptors - antagonists & inhibitors; Toll-Like Receptors - genetics; Toll-Like Receptors - immunology; Toll-Like Receptors - metabolism; Dendritic cell; Toll like receptor; Hematology; Metabolism; Antigen presenting cell
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-10-249540

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.