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

• Published in: Leukemia 2019-07, Vol.33 (7), p.1783-1796
• Main Authors: Jitschin, R., Böttcher, M., Saul, D., Lukassen, S., Bruns, H., Loschinski, R., Ekici, A. B., Reis, A., Mackensen, A., Mougiakakos, D.
• Format: Article
• Language: English
• Subjects: 13/100; 14/19; 42/41; 45/61; 631/532/1542; 692/308/2171; 692/700/565/251; 96/31; Cancer Research; Care and treatment; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Cell Proliferation; Cellular signal transduction; Critical Care Medicine; Disease control; Fatty acids; Genetic aspects; Glycolysis; Glycosylation; Graft versus host reaction; Health aspects; HeLa Cells; Hematology; Homeostasis; Humans; Immunomodulation; Immunoregulation; Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Inflammation; Inflammation - immunology; Inflammation - metabolism; Inflammation - pathology; Intensive; Internal Medicine; Janus kinase; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; Kinases; Licensing; Lymphocytes T; Medicine; Medicine & Public Health; Mesenchymal stem cells; Mesenchymal Stem Cells - immunology; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - pathology; Mesenchyme; Metabolism; N-Acetylglucosamine; O-GlcNAcylation; Oncology; Oxidation; Oxidative phosphorylation; Phenotypes; Phosphorylation; Priming; Signal Transduction; Stat1 protein; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Stem cells; Transcription; Tryptophan; Tryptophan 2,3-dioxygenase; Up-Regulation
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-018-0376-6

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.