Genetic regulation of nitric oxide -dependent mitochondrial metabolism and immune function in dendritic cells
Snyder, Julia P
Snyder, Julia P
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Abstract
Dendritic cell (DC) activation is characterized by a rapid “metabolic switch” towards increased glycolysis that supports maturation. Sustained glycolysis post-activation is a requirement for survival in DC subsets that express inducible nitric oxide synthase (iNOS), due to the production of nitric oxide (NO) which acts as an inhibitor of mitochondrial respiration. Long-term metabolic reprogramming in activated DCs has almost exclusively been studied in the strain C57BL/6, which experience loss of mitochondrial function due to NO accumulation. To assess the conservation of NO-driven metabolic regulation in DCs, we generated and compared cells from C57BL/6 mice to the wild-derived genetically diverse PWD/PhJ (PWD) strain. We show attenuated iNOS induction and significantly lower NO production in PWD DCs. Decreased NO production allows PWD DCs to maintain mitochondrial respiration following activation, and significantly alters their glucose-dependent carbon flux through the TCA cycle compared to C57BL/6 DCs. We utilize a consomic strain which includes the PWD chromosome segment containing the iNOS locus on an otherwise C57BL/6 genetic background to demonstrate that intrinsic differences in the iNOS locus drive differential iNOS regulation. We demonstrate that differential iNOS regulation amongst these strains impacts DC post-activation survival and immune effector functions. These studies provide a more comprehensive understanding of NO-driven metabolic reprogramming in the murine myeloid lineage and establish a natural genetic model for investigating the contribution of NO in regulating the interplay between DC metabolism and immune function.
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Graduate
Graduate
Date
2020-01-01