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 th...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.展开更多
基金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)+3 种基金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 DisordersYoung Taishan Scholar Foundation of Shandong Province(No.tsqn201909175).
文摘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.
