Glycolytic metabolism is essential for CCR7 oligomerization and dendritic cell migration

Abstract

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.

Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis

“…Activation REVIEW SERIES: TRANSLATING IMMUNOMETABOLISM of DCs, either by antigen exposure or stimulation by Toll-like receptor (TLR) ligands, results in a two-phased metabolic shift comprised of an initial glycolytic shift with maintained OXPHOS, followed by elevated glycolysis and the cessation of OXPHOS in long-term activated DCs. Molecularly, TBK-IKKε/AKT signalling pathways and downstream target mammalian target of rapamycin (mTOR) have been strongly implicated in early activation of the glycolytic shift, which can be prevented by adhesion-related kinase (ARK) blockade [62]. Inhibition of glycolysis via HK2 blockade or fatty acid synthase in lipopolysaccharide (LPS)stimulated DCs results in a marked reduction in DC activation and immunogenicity [60].…”

“…During the later stages of DC activation, mTOR-mediated induction of inducible nitric oxide synthase (iNOS) and stabilization of HIF-1α is important for the complete commitment of activated DCs to glycolysis [59,62], with iNOSderived nitric oxide (NO) blocking the electron transport chain (ETC) and sequestering OXPHOS [59] while elevating HIF1α-dependent glycolytic gene expression [62,63,65]. While these metabolic changes remain to be studied in the complex nutrient and/or oxygen-deprived microenvironments, such as those found in the inflamed synovium, similar to macrophages, DC can also sense and respond to extracellular metabolites, such as succinate, butyrate and ATP [33,[66][67][68][69] to potentially trigger a co-ordinated cellular response reflective of the metabolic state of the surrounding microenvironment.…”

“…Activation REVIEW SERIES: TRANSLATING IMMUNOMETABOLISM of DCs, either by antigen exposure or stimulation by Toll-like receptor (TLR) ligands, results in a two-phased metabolic shift comprised of an initial glycolytic shift with maintained OXPHOS, followed by elevated glycolysis and the cessation of OXPHOS in long-term activated DCs. While the early increase in glycolysis is associated with elevated GLUT1 expression [61,62] and lactate production [59][60][61][62][63][64], the increased glucose demand by activated DCs is associated with the requirement of glucose-derived metabolic intermediates into the PPP and fatty acid synthesis to facilitate amino acid and protein synthesis for the secretion of proinflammatory mediators associated with DC activation. Inhibition of glycolysis via HK2 blockade or fatty acid synthase in lipopolysaccharide (LPS)stimulated DCs results in a marked reduction in DC activation and immunogenicity [60].…”

“…Inhibition of glycolysis via HK2 blockade or fatty acid synthase in lipopolysaccharide (LPS)stimulated DCs results in a marked reduction in DC activation and immunogenicity [60]. Molecularly, TBK-IKKε/AKT signalling pathways and downstream target mammalian target of rapamycin (mTOR) have been strongly implicated in early activation of the glycolytic shift, which can be prevented by adhesion-related kinase (ARK) blockade [62]. In the context of RA, while also modulating the T reg /Th17 ratio, BrPA-mediated blockade of HK2 suppressed DC activation and cytokine expression [30], suggesting that the glycolysis pathway may represent a potential therapeutic target in RA.…”

Hypoxia-inducible factor-1α regulation of myeloid cells

“…Ricciardi et al recapitulated these results, showing that monocyte-derived immature DCs grown in hypoxia developed a strong migratory phenotype while dampening proinflammatory cytokine secretion [99]. Guak and colleagues linked this phenomenon to metabolism by demonstrating that both strong and weak stimuli will induce glycolysis in DCs, but only strongly proinflammatory signals will stabilize HIF-1α, leading to a prolonged reprogramming of DC metabolism towards glycolysis [100]. Furthermore, Jantsch et al showed that immature DCs stimulated with LPS under hypoxia, compared to normoxia, have a dramatic increase in T cell costimulatory molecule expression that leads to enhanced lymphocyte proliferation [101].…”