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Stem cell biology

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

Leukemia volume 33, pages 1783–1796 (2019)Cite this article

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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.

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Acknowledgements

RJ was supported by the IZKF Erlangen and funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)- project number 324392634-TRR 221. RL was supported by the “i-Target” doctorate program of the Elite Network Bavaria. DM was supported by the IZKF Erlangen, by the Deutsche Krebshilfe, and the Else Kröner-Fresenius Foundation.

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Authors and Affiliations

  1. Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany

    R. Jitschin, M. Böttcher, D. Saul, H. Bruns, R. Loschinski, A. Mackensen & D. Mougiakakos

  2. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany

    S. Lukassen, A. B. Ekici & A. Reis

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RJ, MB, DS, SL, HB, and RL planned and performed research, compiled and analyzed data, and helped in writing the manuscript. ABE, AR, and AM helped designing experiments and analyzing the data. DM designed the study, analyzed data, and wrote the manuscript.

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Jitschin, R., Böttcher, M., Saul, D. et al. Inflammation-induced glycolytic switch controls suppressivity of mesenchymal stem cells via STAT1 glycosylation. Leukemia 33, 1783–1796 (2019). https://doi.org/10.1038/s41375-018-0376-6

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