PMID- 30679801 OWN - NLM STAT- MEDLINE DCOM- 20191112 LR - 20211108 IS - 1476-5551 (Electronic) IS - 0887-6924 (Linking) VI - 33 IP - 7 DP - 2019 Jul TI - Inflammation-induced glycolytic switch controls suppressivity of mesenchymal stem cells via STAT1 glycosylation. PG - 1783-1796 LID - 10.1038/s41375-018-0376-6 [doi] AB - 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 - Jitschin, R AU - Jitschin R AD - Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Bottcher, M AU - Bottcher M AUID- ORCID: 0000-0003-2911-8830 AD - Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Saul, D AU - Saul D AD - Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Lukassen, S AU - Lukassen S AUID- ORCID: 0000-0001-7045-6327 AD - Institute of Human Genetics, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Bruns, H AU - Bruns H AD - Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Loschinski, R AU - Loschinski R AD - Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Ekici, A B AU - Ekici AB AD - Institute of Human Genetics, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Reis, A AU - Reis A AUID- ORCID: 0000-0002-6301-6363 AD - Institute of Human Genetics, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Mackensen, A AU - Mackensen A AUID- ORCID: 0000-0002-0685-4483 AD - Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Mougiakakos, D AU - Mougiakakos D AD - Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. dimitrios.mougiakakos@uk-erlangen.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190124 PL - England TA - Leukemia JT - Leukemia JID - 8704895 RN - 0 (IDO1 protein, human) RN - 0 (IDO2 protein, human) RN - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase) RN - 0 (STAT1 Transcription Factor) RN - 0 (STAT1 protein, human) RN - EC 2.7.10.2 (JAK1 protein, human) RN - EC 2.7.10.2 (Janus Kinase 1) SB - IM MH - CD8-Positive T-Lymphocytes/*immunology/metabolism/pathology MH - Cell Proliferation MH - *Glycolysis MH - Glycosylation MH - HeLa Cells MH - Humans MH - Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics/metabolism MH - Inflammation/*immunology/metabolism/pathology MH - Janus Kinase 1/genetics/metabolism MH - Mesenchymal Stem Cells/*immunology/metabolism/pathology MH - STAT1 Transcription Factor/genetics/*metabolism MH - Signal Transduction MH - Up-Regulation EDAT- 2019/01/27 06:00 MHDA- 2019/11/13 06:00 CRDT- 2019/01/26 06:00 PHST- 2018/09/03 00:00 [received] PHST- 2018/12/07 00:00 [accepted] PHST- 2018/11/19 00:00 [revised] PHST- 2019/01/27 06:00 [pubmed] PHST- 2019/11/13 06:00 [medline] PHST- 2019/01/26 06:00 [entrez] AID - 10.1038/s41375-018-0376-6 [pii] AID - 10.1038/s41375-018-0376-6 [doi] PST - ppublish SO - Leukemia. 2019 Jul;33(7):1783-1796. doi: 10.1038/s41375-018-0376-6. Epub 2019 Jan 24.