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Cell Rep. 2019 Apr 9;27(2):525-536.e4. doi: 10.1016/j.celrep.2019.03.033.

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

Author information

1
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valladolid, 47005 Valladolid, Spain.
2
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valladolid, 47005 Valladolid, Spain; Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain.
3
Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain.
4
Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
5
Centro para el Desarrollo de la Biotecnología, CSIC, Parque Tecnológico de Boecillo, 47151 Valladolid, Spain.
6
Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain. Electronic address: mscres@ibgm.uva.es.

Abstract

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.

KEYWORDS:

Lands’ cycle; Warburg effect; acetyl-CoA; arachidonic acid; cytokines; fungi; glycolysis; immunometabolism; platelet-activating factor; tricarboxylic acid cycle

PMID:
30970255
DOI:
10.1016/j.celrep.2019.03.033
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