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TLR-driven early glycolytic reprogramming via the kinases TBK1-IKK supports the anabolic demands of dendritic cell activation
Bart Everts1, Eyal Amiel2, Stanley Ching-Cheng Huang1, Amber M Smith1, Chih-Hao Chang1, Wing Y Lam1, Veronika Redmann1, Tori C Freitas3, Julianna Blagih3, Gerritje J W van der Windt1, Maxim N Artyomov1, Russell G Jones4, Erika L Pearce1 & Edward J Pearce1
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 toTLR 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, IKK 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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Dendritic cells (DCs) are highly specialized antigen-presenting cells of myeloid origin with a pivotal role in the initiation and maintenance of adaptive immune responses1. Under noninflammatory conditions, DCs in peripheral tissues exist in a resting immature state, but they express a range of germline-encoded pattern-recognition receptors, including Toll-like receptors (TLRs), that allow them to recognize and rapidly respond to microbial products or inflammatory stimuli. After encountering such danger signals, DCs become activated, a process that involves enhanced capturing and processing of antigens for the stable presentation of antigen-derived peptides in the context of major histocompatibility complex (MHC) class I and class II and induction of the expression of genes encoding chemokine receptors, cytokines and costimulatory molecules. Collectively, these changes enable DCs to promote local inflammation and traffic to T cell zones of secondary lymphoid organs, where they prime T cell responses2.
There is a growing appreciation that changes in the activation of cells of the immune system are coupled to profound changes in cellular metabolism and that cellular...