UDP-glucose regulates dendritic cell mitochondrial respiration via a nitric oxide-dependent mechanism

Bone marrow-derived dendritic cell (BMDC) activation is associated with rewiring of cellular metabolism and concurrent large-scale changes in gene expression promoting a proinflammatory program characterized by expression of inducible nitric oxide synthase and the production of nitric oxide (NO). NO inhibits vital cellular activities including mitochondrial respiration. Mitochondrial respiration inhibition via NO occurs at discrete levels of activating stimulus, termed the mitochondrial respiration threshold, and regulation of this threshold is not fully understood. In this work, we characterize the role of uridine diphosphate glucose as a modulator of NO-mediated mitochondrial respiration inhibition via P2Y14 receptor signaling in stimulated BMDCs. We demonstrate that BMDCs exhibit an enhanced proinflammatory profile in the presence of uridine diphosphate glucose, providing evidence for a new NO regulatory axis in BMDCs. These studies highlight the importance of the growing body of literature supporting metabolites as signaling molecules in activating conditions thus allowing for better modeling of physiologically relevant contexts for myeloid cell encounters with microbial stimuli.