Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation.
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.
Krawczyk
Connie M
CM
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, USA.
Holowka
Thomas
T
Sun
Jie
J
Blagih
Julianna
J
Amiel
Eyal
E
DeBerardinis
Ralph J
RJ
Cross
Justin R
JR
Jung
Euihye
E
Thompson
Craig B
CB
Jones
Russell G
RG
Pearce
Edward J
EJ
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D051193:Toll-Like Receptors; D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt