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

By B. Everts, Eyal Amiel, S. C. Huang, A. Smith, Chih-Hao Chang, W. Lam, Veronika Redmann, T. Freitas, J. Blagih, G. V. D. van der Windt and 4 more. Nature Immunology, 2014

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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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/b2486a2f49fbeb006fa9460b8234144fe46ac509

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Citations in the corpus

Normalization of CD4+ T Cell Metabolism Reverses Lupus (2015, background): “Both glycolysis and mitochondrial metabolism are important for the activation and maturation of dendritic cells (48, 49), which can indirectly affect T cells.”
Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes (2018, background): “Metabolic state is directlymanipulated by cytokine and pattern-recognition receptors, and elevated glycolytic activity has been tied to immune cell activation (Everts et al., 2014; O’Neill and Pearce, 2016).”
Mitochondria in the regulation of innate and adaptive immunity (2015, neutral): “This alteration in metabolism is required to meet the increased bioenergetic and biosynthetic demands of an activated DC, specifically by funneling metabolites into pathways for lipid and protein synthesis (Everts et al., 2014).”
Microglial M1/M2 polarization and metabolic states (2016, background): “As observed in other immune cells (Everts et al., 2014), the data suggest that activation of microglia goes through two metabolic steps.”
Repurposing mitochondria from ATP production to ROS generation drives a pro-inflammatory phenotype in macrophages that depends on succinate oxidation by complex II (2016, background): “…necessary er 6, 2016 Crown Copyright ª 2016 Published by Elsevier Inc. 457 for the production and secretion of key proteins essential for DC activation (Everts et al., 2014) and to prevent apoptosis in the face of a lowered level of ATP production by oxidative phosphorylation (Everts et al., 2012).”
Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation (2016, background): “Macrophage activation by lipopolysaccharide (LPS) is accompa- nied by marked metabolic changes including upregulation of aer- obic glycolysis (Everts et al., 2014), impaired mitochondrial respi- ration, disruption of the TCA cycle (Jha et al., 2015), and accumulation of succinate (Kelly andO’Neill,…”
Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology (2020, background): “In dendritic cells (DCs), metabolic reprogramming to a high-glycolytic phenotype is necessary for DC activation and regulates DC cytokine production and antigen presenting capability (Krawczyk et al. 2010; Everts et al. 2014).”