Tricarboxylic Acid Cycle Activity and Remodeling of Glycerophosphocholine Lipids Support Cytokine Induction in Response to Fungal Patterns

Abstract

Summary: Increased glycolysis parallels immune cell activation, but the role of pyruvate remains largely unexplored. We found that stimulation of dendritic cells with the fungal surrogate zymosan causes decreases of pyruvate, citrate, itaconate, and α-ketoglutarate, while increasing oxaloacetate, succinate, lactate, oxygen consumption, and pyruvate dehydrogenase activity. Expression of IL10 and IL23A (the gene encoding the p19 chain of IL-23) depended on pyruvate dehydrogenase activity. Mechanistically, pyruvate reinforced histone H3 acetylation, and acetate rescued the effect of mitochondrial pyruvate carrier inhibition, most likely because it is a substrate of the acetyl-CoA producing enzyme ACSS2. Mice lacking the receptor of the lipid mediator platelet-activating factor (PAF; 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine) showed reduced production of IL-10 and IL-23 that is explained by the requirement of acetyl-CoA for PAF biosynthesis and its ensuing autocrine function. Acetyl-CoA therefore intertwines fatty acid remodeling of glycerophospholipids and energetic metabolism during cytokine induction. : Márquez et al. show a regulatory mechanism of cytokine induction that involves acetylation of histones and a self-amplifying loop through the platelet-activating factor receptor. This mechanism links phospholipid remodeling in the Lands’ cycle with energetic metabolism in the tricarboxylic acid cycle. Acetyl-CoA is the nexus between both cycles. Keywords: acetyl-CoA, arachidonic acid, cytokines, fungi, glycolysis, immunometabolism, Lands’ cycle, platelet-activating factor, tricarboxylic acid cycle, Warburg effect