Glycolytic metabolism is essential for CCR7 oligomerization and dendritic cell migration

Dendritic cells (DCs) are first responders of the innate immune system that integrate signals from external stimuli to direct context-specific immune responses. Current models suggest that an active switch from mitochondrial metabolism to glycolysis accompanies DC activation to support the anabolic...

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Bibliographic Details
Published in:	Nature communications 2018-06, Vol.9 (1), p.2463-12, Article 2463
Main Authors:	Guak, Hannah, Al Habyan, Sara, Ma, Eric H, Aldossary, Haya, Al-Masri, Maia, Won, So Yoon, Ying, Thomas, Fixman, Elizabeth D, Jones, Russell G, McCaffrey, Luke M, Krawczyk, Connie M
Format:	Article
Language:	eng
Subjects:	AKT protein Animals Bioenergetics CC chemokine receptors CCR7 protein Cell activation Cell adhesion & migration Cell Differentiation Cell migration Cell Movement - immunology Cell Shape - physiology Cell size Dendritic cells Dendritic Cells - immunology Dendritic Cells - physiology Drainage Elongation Emergency medical services External stimuli Female Glycolysis Glycolysis - physiology Immune response Immune system Inflammation Innate immunity Leukocyte migration Lymph nodes Lymph Nodes - cytology Metabolism Mice Mice, Inbred BALB C Mice, Inbred C57BL Mitochondria Mitochondria - metabolism Oligomerization Oxidative metabolism Oxidative Phosphorylation Phenotypes Receptors, CCR7 - metabolism Stimuli TOR protein
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Summary:	Dendritic cells (DCs) are first responders of the innate immune system that integrate signals from external stimuli to direct context-specific immune responses. Current models suggest that an active switch from mitochondrial metabolism to glycolysis accompanies DC activation to support the anabolic requirements of DC function. We show that early glycolytic activation is a common program for both strong and weak stimuli, but that weakly activated DCs lack long-term HIF-1α-dependent glycolytic reprogramming and retain mitochondrial oxidative metabolism. Early induction of glycolysis is associated with activation of AKT, TBK, and mTOR, and sustained activation of these pathways is associated with long-term glycolytic reprogramming. We show that inhibition of glycolysis impaired maintenance of elongated cell shape, DC motility, CCR7 oligomerization, and DC migration to draining lymph nodes. Together, our results indicate that early induction of glycolysis occurs independent of pro-inflammatory phenotype, and that glycolysis supports DC migratory ability regardless of mitochondrial bioenergetics.
ISSN:	2041-1723 2041-1723