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Glucocorticoid receptor modulates myeloid-derived suppressor cell function via mitochondrial metabolism in immune thrombocytopenia

Cellular & Molecular Immunology volume 19, pages 764–776 (2022)Cite this article

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Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature cells and natural inhibitors of adaptive immunity. Intracellular metabolic changes in MDSCs exert a direct immunological influence on their suppressive activity. Our previous study demonstrated that high-dose dexamethasone (HD-DXM) corrected the functional impairment of MDSCs in immune thrombocytopenia (ITP); however, the MDSC population was not restored in nonresponders, and the mechanism remained unclear. In this study, altered mitochondrial physiology and reduced mitochondrial gene transcription were detected in MDSCs from HD-DXM nonresponders, accompanied by decreased levels of carnitine palmitoyltransferase-1 (CPT-1), a rate-limiting enzyme in fatty acid oxidation (FAO). Blockade of FAO with a CPT-1 inhibitor abolished the immunosuppressive function of MDSCs in HD-DXM responders. We also report that MDSCs from ITP patients had lower expression of the glucocorticoid receptor (GR), which can translocate into mitochondria to regulate the transcription of mitochondrial DNA (mtDNA) as well as the level of oxidative phosphorylation. It was confirmed that the expression of CPT-1 and mtDNA-encoded genes was downregulated in GR-siRNA-treated murine MDSCs. Finally, by establishing murine models of active and passive ITP via adoptive transfer of DXM-modulated MDSCs, we confirmed that GR-silenced MDSCs failed to alleviate thrombocytopenia in mice with ITP. In conclusion, our study indicated that impaired aerobic metabolism in MDSCs participates in the pathogenesis of glucocorticoid resistance in ITP and that intact control of MDSC metabolism by GR contributes to the homeostatic regulation of immunosuppressive cell function.

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All datasets generated and/or analyzed during the current study are available from the corresponding authors.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81900121, 81770133, 81973994, and 81770114), Major Research Plan of National Natural Science Foundation of China (No. 91942306), Clinical Research Center of Shandong University (No. 2020SDUCRCC009), Graduate Education Reform Project of Shandong University (No. XYJG2020141), State Key Clinical Specialty of China for Blood Disorders, and Young Taishan Scholar Foundation of Shandong Province (No. tsqn201909175).

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  1. These authors contributed equally: Yu Hou, Jie Xie, Shuwen Wang.

Authors and Affiliations

  1. Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China

    Yu Hou, Jie Xie, Shuwen Wang, Lingjun Wang, Haoyi Wang, Xiaofei Ni, Shaoqiu Leng, Ming Hou & Jun Peng

  2. Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China

    Yu Hou, Guosheng Li, Ming Hou & Jun Peng

  3. Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China

    Jie Xie & Daqi Li

  4. Leading Research Group of Scientific Innovation, Department of Science and Technology of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China

    Ming Hou

  5. Advanced Medical Research Institute, Shandong University, Jinan, China

    Jun Peng

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Contributions

YH, JP and JX designed the research and wrote the manuscript. JX, SW, LW, HW, XN and SL performed the experiments and analyzed the data. YH, GL and DL provided technical and instrumental support. YH, JP and MH provided conceptual advice and edited the manuscript. YH and JP supervised the study and provided funding support.

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Correspondence to Yu Hou or Jun Peng.

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Hou, Y., Xie, J., Wang, S. et al. Glucocorticoid receptor modulates myeloid-derived suppressor cell function via mitochondrial metabolism in immune thrombocytopenia. Cell Mol Immunol 19, 764–776 (2022). https://doi.org/10.1038/s41423-022-00859-0

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