Increased glycolysis parallels immune cell activation, but the role of pyruvate flux remains largely unexplored. We show that stimulation of dendritic cells with the fungal surrogate zymosan induces a drop of pyruvate, citrate, itaconate, and α-ketoglutarate, as well as an increase in oxaloacetate, succinate, lactate, oxygen consumption, and activation of pyruvate dehydrogenase activity. The expression of IL10 and IL23A (the gene encoding the p19 chain of IL-23) depended on mitochondrial activity. Pyruvate underpinned histone H3 acetylation and acetate rescued the effect of mitochondrial pyruvate carrier inhibition, most likely because of compensation by the acetyl-CoA producing enzyme ACSS2. Mice lacking the receptor of the lipid mediator PAF (1-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine), showed a reduced production of IL-10 and IL-23 that is explained by the requirement of acetyl-CoA for PAF biosynthesis and the ensuing autocrine function of PAF. Acetyl-CoA is the nexus in the intertwining of phospholipid recycling and energetic metabolism involved in cytokine induction.
Márquez, Saioa and Fernández, José Javier and Mancebo, Cristina and Herrero-Sánchez, Carmen and Alonso, Sara and Sandoval, Tito A. and Prados, Macarena Rodríguez and Cubillos-Ruiz, Juan R. and Montero, Olimpio and Fernández, Nieves and Sánchez Crespo, Mariano, Tricarboxylic Acid Cycle Activity and Glycerophosphocholine Lipid Recycling Support Dendritic Cell Cytokine Induction in Response to Fungal Patterns (October 30, 2018). Available at SSRN: https://ssrn.com/abstract=3275283 or http://dx.doi.org/10.2139/ssrn.3275283
This version of the paper has not been formally peer reviewed.
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