Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells

B Everts, E Amiel, GJW Van Der Windt… - Blood, The Journal …, 2012 - ashpublications.org
B Everts, E Amiel, GJW Van Der Windt, TC Freitas, R Chott, KE Yarasheski, EL Pearce
Blood, The Journal of the American Society of Hematology, 2012ashpublications.org
TLR agonists initiate a rapid activation program in dendritic cells (DCs) that requires support
from metabolic and bioenergetic resources. We found previously that TLR signaling
promotes aerobic glycolysis and a decline in oxidative phosphorylation (OXHPOS) and that
glucose restriction prevents activation and leads to premature cell death. However, it
remained unclear why the decrease in OXPHOS occurs under these circumstances. Using
real-time metabolic flux analysis, in the present study, we show that mitochondrial activity is …
Abstract
TLR agonists initiate a rapid activation program in dendritic cells (DCs) that requires support from metabolic and bioenergetic resources. We found previously that TLR signaling promotes aerobic glycolysis and a decline in oxidative phosphorylation (OXHPOS) and that glucose restriction prevents activation and leads to premature cell death. However, it remained unclear why the decrease in OXPHOS occurs under these circumstances. Using real-time metabolic flux analysis, in the present study, we show that mitochondrial activity is lost progressively after activation by TLR agonists in inflammatory blood monocyte–derived DCs that express inducible NO synthase. We found that this is because of inhibition of OXPHOS by NO and that the switch to glycolysis is a survival response that serves to maintain ATP levels when OXPHOS is inhibited. Our data identify NO as a profound metabolic regulator in inflammatory monocyte–derived DCs.
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