Inflammation-induced glycolytic switch controls suppressivity of mesenchymal stem cells via STAT1 glycosylation

Journal article


Publication Details

Author(s): Jitschin R, Böttcher M, Saul D, Lukassen S, Bruns H, Loschinski R, Ekici AB, Reis A, Mackensen A, Mougiakakos D
Journal: Leukemia
Publication year: 2019
ISSN: 0887-6924


Abstract

Mesenchymal stem cells (MSCs) represent key contributors to tissue homeostasis and promising therapeutics for hyperinflammatory conditions including graft-versus-host disease. Their immunomodulatory effects are controlled by microenvironmental signals. The MSCs' functional response towards inflammatory cues is known as MSC-"licensing" and includes indoleamine 2,3-dioxygenase (IDO) upregulation. MSCs use tryptophan-depleting IDO to suppress T-cells. Increasing evidence suggests that several functions are (co-)determined by the cells' metabolic commitment. MSCs are capable of both, high levels of glycolysis and of oxidative phosphorylation. Although several studies have addressed alterations of the immune regulatory phenotype elicited by inflammatory priming metabolic mechanisms controlling this process remain unknown. We demonstrate that inflammatory MSC-licensing causes metabolic shifts including enhanced glycolysis and increased fatty acid oxidation. Yet, only interfering with glycolysis impacts IDO upregulation and impedes T-cell-suppressivity. We identified the Janus kinase (JAK)/signal transducer and activator of transcription (STAT)1 pathway as a regulator of both glycolysis and IDO, and show that enhanced glucose turnover is linked to abundant STAT1 glycosylation. Inhibiting the responsible O-acetylglucosamine (O-GlcNAc) transferase abolishes STAT1 activity together with IDO upregulation. Our data suggest that STAT1-O-GlcNAcylation increases its stability towards degradation thus sustaining downstream effects. This pathway could represent a target for interventions aiming to enhance the MSCs' immunoregulatory potency.


FAU Authors / FAU Editors

Böttcher, Martin Dr. rer. nat.
Medizinische Klinik 5 - Hämatologie und Internistische Onkologie
Bruns, Heiko PD Dr.
Medizinische Klinik 5 - Hämatologie und Internistische Onkologie
Ekici, Arif Bülent Dr. rer. nat.
Humangenetisches Institut
Böttcher-Loschinski, Romy Dr. rer. nat.
Medizinische Klinik 5 - Hämatologie und Internistische Onkologie
Lukassen, Sören
Professur für Humangenetik
Mackensen, Andreas Prof. Dr.
Lehrstuhl für Innere Medizin V
Mougiakakos, Dimitrios
Professur für Hämatologie/Onkologie mit dem Schwerpunkt Tumorimmunologie


How to cite

APA:
Jitschin, R., Böttcher, M., Saul, D., Lukassen, S., Bruns, H., Loschinski, R.,... Mougiakakos, D. (2019). Inflammation-induced glycolytic switch controls suppressivity of mesenchymal stem cells via STAT1 glycosylation. Leukemia. https://dx.doi.org/10.1038/s41375-018-0376-6

MLA:
Jitschin, R., et al. "Inflammation-induced glycolytic switch controls suppressivity of mesenchymal stem cells via STAT1 glycosylation." Leukemia (2019).

BibTeX: 

Last updated on 2019-21-07 at 08:01