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TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation

Nature Immunology volume 15, pages 323332 (2014) | Download Citation

Abstract

The ligation of Toll-like receptors (TLRs) leads to rapid activation of dendritic cells (DCs). However, the metabolic requirements that support this process remain poorly defined. We found that DC glycolytic flux increased within minutes of exposure to TLR agonists and that this served an essential role in supporting the de novo synthesis of fatty acids for the expansion of the endoplasmic reticulum and Golgi required for the production and secretion of proteins that are integral to DC activation. Signaling via the kinases TBK1, IKKɛ and Akt was essential for the TLR-induced increase in glycolysis by promoting the association of the glycolytic enzyme HK-II with mitochondria. In summary, we identified the rapid induction of glycolysis as an integral component of TLR signaling that is essential for the anabolic demands of the activation and function of DCs.

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Acknowledgements

We thank members of the Pearce laboratory for discussions; H. Virgin for support of the 14C-glucose–tracing experiments; W. Beatty and the Molecular Microbiology Imaging Facility for technical assistance with electron microscopy; and G. Bridon and B. Faubert for help with the glucose-tracing experiments. Some observations reported here were made while B.E., E.A., T.C.F., G.J.W.v.d.W., E.L.P. and E.J.P. were at the Trudeau Institute; we thank the institute for its support during that time. Supported by the US National Institutes of Health (AI53825 and CA164062 to E.J.P.; AI091965 and CA158823 to E.L.P.; and AI049823 to E.A.), the Netherlands Organisation for Scientific Research (B.E. and G.J.W.v.d.W.) and The Arthritis Society of Canada (R.G.J.).

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Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Bart Everts
    • , Stanley Ching-Cheng Huang
    • , Amber M Smith
    • , Chih-Hao Chang
    • , Wing Y Lam
    • , Veronika Redmann
    • , Gerritje J W van der Windt
    • , Maxim N Artyomov
    • , Erika L Pearce
    •  & Edward J Pearce
  2. Department of Medical Laboratory and Radiation Sciences, University of Vermont, Burlington, Vermont, USA.

    • Eyal Amiel
  3. Trudeau Institute, Saranac Lake, New York, USA.

    • Tori C Freitas
    •  & Julianna Blagih
  4. Department of Physiology, McGill University, Montreal, Quebec, Canada.

    • Russell G Jones

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Contributions

B.E., E.A., S.C.-C.H., C.-H.C., G.J.W.v.d.W., R.G.J., E.L.P. and E.J.P. designed experiments; B.E., E.A., S.C.-C.H., C.-H.C., A.M.S., W.Y.L., V.R., T.C.F. and J.B. did experiments. B.E., E.A., S.C.-C.H., J.B., R.G.J., M.N.A., E.L.P. and E.J.P. analyzed data; and B.E. and E.J.P. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Edward J Pearce.

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https://doi.org/10.1038/ni.2833

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