High mitochondrial respiration and glycolytic capacity represent a metabolic phenotype of human tolerogenic dendritic cells.
Human dendritic cells (DCs) regulate the balance between immunity and tolerance through selective activation by environmental and pathogen-derived triggers. To characterize the rapid changes that occur during this process, we analyzed the underlying metabolic activity across a spectrum of functional DC activation states, from immunogenic to tolerogenic. We found that in contrast to the pronounced proinflammatory program of mature DCs, tolerogenic DCs displayed a markedly augmented catabolic pathway, related to oxidative phosphorylation, fatty acid metabolism, and glycolysis. Functionally, tolerogenic DCs demonstrated the highest mitochondrial oxidative activity, production of reactive oxygen species, superoxide, and increased spare respiratory capacity. Furthermore, assembled, electron transport chain complexes were significantly more abundant in tolerogenic DCs. At the level of glycolysis, tolerogenic and mature DCs showed similar glycolytic rates, but glycolytic capacity and reserve were more pronounced in tolerogenic DCs. The enhanced glycolytic reserve and respiratory capacity observed in these DCs were reflected in a higher metabolic plasticity to maintain intracellular ATP content. Interestingly, tolerogenic and mature DCs manifested substantially different expression of proteins involved in the fatty acid oxidation (FAO) pathway, and FAO activity was significantly higher in tolerogenic DCs. Inhibition of FAO prevented the function of tolerogenic DCs and partially restored T cell stimulatory capacity, demonstrating their dependence on this pathway. Overall, tolerogenic DCs show metabolic signatures of increased oxidative phosphorylation programing, a shift in redox state, and high plasticity for metabolic adaptation. These observations point to a mechanism for rapid genome-wide reprograming by modulation of underlying cellular metabolism during DC differentiation.
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673; Singapore Immunology Network, Singapore 138648; and.
Frano
F
Malinarich
Singapore Immunology Network, Singapore 138648; and.
Kaibo
K
Duan
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673; Singapore Immunology Network, Singapore 138648; and.
Raudhah Abdull
RA
Hamid
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673; Singapore Immunology Network, Singapore 138648; and.
Au
A
Bijin
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673; Singapore Immunology Network, Singapore 138648; and.
Wu Xue
WX
Lin
Singapore Immunology Network, Singapore 138648; and.
Michael
M
Poidinger
Singapore Immunology Network, Singapore 138648; and.
Anna-Marie
AM
Fairhurst
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673; Singapore Immunology Network, Singapore 138648; and Institute of Biomedical Studies, Baylor University, Waco, TX 76798 jeconnolly@imcb.a-star.edu.sg.
John E
JE
Connolly
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics; D000102:Acetyl-CoA C-Acyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics; D019748:Carbon-Carbon Double Bond Isomerases / Q000037:antagonists & inhibitors / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D045222:Electron Transport Chain Complex Proteins / Q000096:biosynthesis / Q000378:metabolism; D004746:Enoyl-CoA Hydratase / Q000037:antagonists & inhibitors / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
D045222:Electron Transport Chain Complex Proteins; D005227:Fatty Acids; C038784:fatty acid oxidation complex; D013481:Superoxides; D015094:3-Hydroxyacyl CoA Dehydrogenases; D000102:Acetyl-CoA C-Acyltransferase; D004746:Enoyl-CoA Hydratase; D019998:Racemases and Epimerases; D019748:Carbon-Carbon Double Bond Isomerases