UDP-glucose Regulates Dendritic Cell Mitochondrial Respiration via a Nitric Oxide-dependent Mechanism

Abstract Dendritic cells (DCs) are key innate immune specialized in fine tuning an response. Activation of DCs through Toll-Like Receptors (TLRs) is accompanied by a metabolic switch to increased use glycolytic metabolism fueled carbohydrates glucose and glycogen. Our lab has shown that require glycogen perform their effector functions including: production cytokines inflammatory mediators, antigen presentation T cells, initiation the cell-mediated Recent studies macrophages showed secondary metabolite synthetic pathway, uridine diphosphate (UDP-glucose), upregulated TLR4 stimulation. UDP-glucose exits cell signals autocrine manner its specific purinergic receptor P2Y 14. Additionally, 14R signaling modulates expression proinflammatory pathways including upregulation inducible nitric oxide synthase (iNOS). Activated bone marrow-derived (BMDCs) upregulate iNOS produce (NO), which pleiotropic effects, inhibiting mitochondrial respiration. Therefore, we hypothesized UDP-glucose/P2Y 14R/iNOS axis regulates BMDC metabolism, further ramifications on DC survival phenotypes. To investigate impact as molecule, characterized gene transcript protein levels, well functional outcomes cell. These bolster phenotypes inhibition respiration leading exacerbated death. Supported grants from NIH (R01 AI158710-01, 1R21AI135385-01A1) UVM (COBRE VCIID Funding Support Pilot Project)