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Tricarboxylic Acid Cycle Activity and Glycerophosphocholine Lipid Recycling Support Dendritic Cell Cytokine Induction in Response to Fungal Patterns

43 Pages Posted: 30 Oct 2018 Publication Status: Under Review

See all articles by Saioa Márquez

Saioa Márquez

University of Valladolid - Department of Biochemistry and Molecular Biology

José Javier Fernández

University of Valladolid - Department of Biochemistry and Molecular Biology

Cristina Mancebo

Universidad de Valladolid - Departamento de Bioquímica y Biología Molecular

Carmen Herrero-Sánchez

Universidad de Valladolid - Instituto de Biología y Genética Molecular

Sara Alonso

Universidad de Valladolid - Instituto de Biología y Genética Molecular

Tito A. Sandoval

Cornell University - Department of Obstetrics and Gynecology

Macarena Rodríguez Prados

University of Valladolid - Department of Biochemistry and Molecular Biology

Juan R. Cubillos-Ruiz

Cornell University - Department of Obstetrics and Gynecology

Olimpio Montero

Parque Tecnológico de Boecillo - Centro para el Desarrollo de la Biotecnología

Nieves Fernández

University of Valladolid - Department of Biochemistry and Molecular Biology

Mariano Sánchez Crespo

Universidad de Valladolid - Instituto de Biología y Genética Molecular

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Abstract

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.

Suggested Citation

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.

Saioa Márquez

University of Valladolid - Department of Biochemistry and Molecular Biology

8 C/Plaza de Santa Cruz
Valladolid, Valladolid 47002
Spain

José Javier Fernández

University of Valladolid - Department of Biochemistry and Molecular Biology

8 C/Plaza de Santa Cruz
Valladolid, Valladolid 47002
Spain

Cristina Mancebo

Universidad de Valladolid - Departamento de Bioquímica y Biología Molecular

8 C/Plaza de Santa Cruz
Valladolid, Valladolid 47002
Spain

Carmen Herrero-Sánchez

Universidad de Valladolid - Instituto de Biología y Genética Molecular

8 C/Plaza de Santa Cruz
Valladolid, Valladolid 47002
Spain

Sara Alonso

Universidad de Valladolid - Instituto de Biología y Genética Molecular

8 C/Plaza de Santa Cruz
Valladolid, Valladolid 47002
Spain

Tito A. Sandoval

Cornell University - Department of Obstetrics and Gynecology

1300 York Avenue
New York, NY 10065
United States

Macarena Rodríguez Prados

University of Valladolid - Department of Biochemistry and Molecular Biology

8 C/Plaza de Santa Cruz
Valladolid, Valladolid 47002
Spain

Juan R. Cubillos-Ruiz

Cornell University - Department of Obstetrics and Gynecology

1300 York Avenue
New York, NY 10065
United States

Olimpio Montero

Parque Tecnológico de Boecillo - Centro para el Desarrollo de la Biotecnología

47151-Valladolid
Spain

Nieves Fernández

University of Valladolid - Department of Biochemistry and Molecular Biology

8 C/Plaza de Santa Cruz
Valladolid, Valladolid 47002
Spain

Mariano Sánchez Crespo (Contact Author)

Universidad de Valladolid - Instituto de Biología y Genética Molecular ( email )

8 C/Plaza de Santa Cruz
Valladolid, Valladolid 47002
Spain

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