PLATELETS AND THROMBOPOIESIS High-dose dexamethasone corrects impaired myeloid-derived suppressor cell function via Ets 1 in immune thrombocytopenia

• The impaired suppressive function of myeloid-derived suppressor cells plays a role in the pathogenesis of immune thrombocytopenia. • The effect of dexamethasone in correcting dysfunction of myeloid-derived suppressor cells suggests a new therapeutic mechanism of high-dose dexamethasone in patients with immune thrombocytopenia. Myeloid-derivedsuppressor cells (MDSCs)areheterogeneous immaturecells andnatural inhibitorsof adaptive immunity. In this study, theMDSCpopulationwasevaluated inadult patients with primary immune thrombocytopenia (ITP), where cell-mediated immune mechanisms are involved in platelet destruction. Our data demonstrated that both the numbers and suppressive functions of MDSCswere impaired in the peripheral blood and spleens of patients with ITP compared with healthy control patients. High-dose dexamethasone (HD-DXM) treatment rescued MDSC numbers in patients with ITP. And DXM modulation promoted the suppressive function of MDSCs induced in vitro. Moreover, the expression of interleukin 10 and transforming growth factor b was significantly upregulated in DXM-modulated MDSCs compared with the unmodulated cultures. DXMmodulated MDSCs inhibited autologous CD4 T-cell proliferation and significantly attenuated cytotoxic T lymphocyte–mediated platelet lysis, further indicating enhanced control over T-cell responses. Elevated expression of the transcription factor Ets1 was identified in DXM-modulated MDSCs. Transfection of Ets-1 small interfering RNA efficiently blocked regulatory effects of MDSCs, which almost offset the augmentation of MDSC function by DXM. Meanwhile, splenocytes from CD61 knockout mice immunized with CD61 platelets were transferred into severe combined immunodeficient (SCID) mouse recipients (C57/B6 background) to induce amurinemodel of severe ITP.We passively transferred theDXM-modulatedMDSCs induced from bone marrow of wild-type C57/B6 mice into the SCID mouse recipients, which significantly increased platelet counts in vivo comparedwith those receiving splenocyte engraftment alone. These findings suggested that impairedMDSCs are involved in the pathogenesis of ITP, and that HD-DXM corrected MDSC functions via a mechanism underlying glucocorticoid action and Ets1. (Blood. 2016;127(12):1587-1597)