In this issue of Blood, Hou et al show the involvement of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of immune thrombocytopenia (ITP) and identify a novel mechanism by which high-dose dexamethasone (HD-DXM) promotes MDSC expansion and function and correlates with increased platelet counts.1 

Enhanced helper T-cell activity facilitating autoantibody-mediated platelet clearance and CTL-mediated platelet (Plt)/megakaryocyte (MK) destruction is involved in the cellular immunopathogenesis of ITP. DXM-modulated MDSCs (CD33+CD11b+HLA-DRlow) from in vitro cultures (peripheral blood mononuclear cells [PBMCs] supplemented with interleukin-6 [IL-6], granulocyte macrophage CSF [GM-CSF]) results in elevated levels of functional molecules (ARG, NO), upregulation of suppressive cytokines (IL-10, transforming growth factor-β [TGF-β]) and eventually inhibition of CD4+ T-cell proliferation as well as CTL-induced cytotoxicity. In an ITP murine model (splenocyte engraftment from immune CD61 knockout [KO] mice), transfer of DXM-modulated CD11b+Gr1+ MDSCs (bone marrow [BM] supplemented with IL-6, macrophage-CSF [M-CSF]) alleviated the thrombocytopenia in severe combined immunodeficient mice. Both DXM-modulated human MDSCs and posttransfer murine splenocytes show increased expression of Ets1.

Enhanced helper T-cell activity facilitating autoantibody-mediated platelet clearance and CTL-mediated platelet (Plt)/megakaryocyte (MK) destruction is involved in the cellular immunopathogenesis of ITP. DXM-modulated MDSCs (CD33+CD11b+HLA-DRlow) from in vitro cultures (peripheral blood mononuclear cells [PBMCs] supplemented with interleukin-6 [IL-6], granulocyte macrophage CSF [GM-CSF]) results in elevated levels of functional molecules (ARG, NO), upregulation of suppressive cytokines (IL-10, transforming growth factor-β [TGF-β]) and eventually inhibition of CD4+ T-cell proliferation as well as CTL-induced cytotoxicity. In an ITP murine model (splenocyte engraftment from immune CD61 knockout [KO] mice), transfer of DXM-modulated CD11b+Gr1+ MDSCs (bone marrow [BM] supplemented with IL-6, macrophage-CSF [M-CSF]) alleviated the thrombocytopenia in severe combined immunodeficient mice. Both DXM-modulated human MDSCs and posttransfer murine splenocytes show increased expression of Ets1.

Autoimmune disease can occur when the natural immunosuppressive cells that keep autoreactive lymphocytes in check are lost or are suppressed themselves. For example, impaired CD4+CD25+Foxp3high T regulatory cells (Tregs) have emerged as significant contributors to the pathogenesis of various autoimmune disorders including ITP. Other immunosuppressive cells called MDSCs are a morphologically and functionally heterogeneous population of myeloid progenitor cells that are also potent regulators of adaptive immunity.2  The most striking feature of MDSCs is their ability to inhibit T-cell proliferation through depleting nutrients required for the functional enzymatic activity of arginase-1 (Arg-1) and/or nitric oxide (NO) production.3,4  Although initially described in malignancies, MDSCs are also present in inflammatory and autoimmune settings. Several culture conditions for the in vitro generation of MDSCs have been developed using a combination of cytokines and colony-stimulating factors (CSFs). The effects of common immunosuppressive therapies, such as glucocorticoids (GCs), on MDSC development are unknown.

Since the initial success of HD-DXM in ITP management, there has been increased interest in understanding the mechanisms involved in the ability of steroids to raise platelet counts. In 2007, Ling et al confirmed that a 4-day regimen of HD-DXM expanded both Tregs and myeloid dendritic cells in ITP, suggesting that GCs restore regulatory cells in autoimmune scenarios.5  Similarly, GCs have been found to induce a specific monocytic phenotype with anti-inflammatory properties in humans and a corresponding subset resembling tumor-derived MDSCs in mice.6  In the present study, HD-DXM successfully increased the number of MDSCs in ITP patients. This finding was further demonstrated by an augmentation of in vitro–generated patient MDSCs. More intriguingly, HD-DXM was capable of improving the various immunomodulatory processes of MDSCs, including but not limited to the production of lymphocytes.1  Thus, the cell-mediated destruction of platelets (and perhaps megakaryocytes) involving active T helper cells and cytotoxic T lymphocytes (CTLs) may be controlled by DXM-modulated MDSCs in ITP.

Hou et al recruited 21 patients with primary ITP to receive HD-DXM (40 mg per day) for 4 consecutive days and compared the percentage and the cytoplasmic content of effector molecules of peripheral blood MDSCs after treatment with that of pretreatment samples and samples from healthy control individuals (see figure). The authors also innovatively evaluated the population of splenic MDSCs in 5 patients with ITP as well as controls. The data presented are persuasive and offer a different perspective on the previously established understanding of ITP pathogenesis, confirming the contribution of impaired MDSCs in the loss of immune balance and the efficacy of HD-DXM in raising the MDSC number. It also appears that in some patients with elevated percentages of MDSCs, there is a more likely tendency to achieve remission which also suggests a possible correlation between MDSC improvement and remission rate, but this needs to be further explored.

Recently, Liao et al investigated GC-dependent mechanisms of MDSC development and confirmed that DXM potentiates MDSC cell function in prolonging allograft survival.7  Now, Hou et al not only provided solid evidence that DXM potentiates MDSC cell function in showing functional improvement of DXM-modulated MDSCs in ITP, but also identified a molecular mechanism underlying the GC’s action on MDSCs. Like other GCs, DXM modulates cell fate via the glucocorticoid receptor (GR) and altering gene expression patterns particularly the Ets transcription factor family which can act as a molecular switch to regulate steroid activities.8  According to the authors, upon silencing Ets1 in DXM-modulated MDSCs, the suppression of CD4+ T-cell proliferation was significantly quenched which indicated a possible explanation for DXM-mediated MDSC improvement via Ets1. The study was thoughtfully designed as shown by the inclusion of in vivo experiments in a murine model of severe ITP.9  ITP mice that received passive transfer of DXM-modulated murine MDSCs had significantly increased platelet counts and a higher survival rate. Like the in vitro situation, the ITP mice transferred with DXM-modulated MDSCs also had significantly higher expression levels of Ets1 compared with controls.

This research sheds new light on the therapeutic application of MDSCs via in vitro expansion followed by cell transplantation to restore immune tolerance in patients with ITP. The findings provide novel, mechanistic insights linking the necessary role of MDSCs in the pathogenesis and steroid management of ITP and perhaps other immune-related diseases. Future studies that investigate the GC-mediated mechanisms of MDSC expansion should be of great benefit in the clinic.

Conflict-of-interest disclosure: The author declares no competing financial interests.

REFERENCES

1
Hou
 
Y
Feng
 
Q
Xu
 
M
, et al. 
High-dose dexamethasone corrects impaired myeloid-derived suppressor cell function via Ets1 in immune thrombocytopenia.
Blood
2016
, vol. 
127
 
12
(pg. 
1587
-
1597
)
2
Gabrilovich
 
DI
Nagaraj
 
S
Myeloid-derived suppressor cells as regulators of the immune system.
Nat Rev Immunol
2009
, vol. 
9
 
3
(pg. 
162
-
174
)
3
Bronte
 
V
Zanovello
 
P
Regulation of immune responses by L-arginine metabolism.
Nat Rev Immunol
2005
, vol. 
5
 
8
(pg. 
641
-
654
)
4
Highfill
 
SL
Rodriguez
 
PC
Zhou
 
Q
, et al. 
Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13.
Blood
2010
, vol. 
116
 
25
(pg. 
5738
-
5747
)
5
Ling
 
Y
Cao
 
X
Yu
 
Z
Ruan
 
C
Circulating dendritic cells subsets and CD4+Foxp3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasome.
Eur J Haematol
2007
, vol. 
79
 
4
(pg. 
310
-
316
)
6
Varga
 
G
Ehrchen
 
J
Tsianakas
 
A
, et al. 
Glucocorticoids induce an activated, anti-inflammatory monocyte subset in mice that resembles myeloid-derived suppressor cells.
J Leukoc Biol
2008
, vol. 
84
 
3
(pg. 
644
-
650
)
7
Liao
 
J
Wang
 
X
Bi
 
Y
, et al. 
Dexamethasone potentiates myeloid-derived suppressor cell function in prolonging allograft survival through nitric oxide.
J Leukoc Biol
2014
, vol. 
96
 
5
(pg. 
675
-
684
)
8
Kassel
 
O
Herrlich
 
P
Crosstalk between the glucocorticoid receptor and other transcription factors: molecular aspects.
Mol Cell Endocrinol
2007
, vol. 
275
 
1-2
(pg. 
13
-
29
)
9
Chow
 
L
Aslam
 
R
Speck
 
ER
, et al. 
A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell-mediated responses that are differentially sensitive to therapy.
Blood
2010
, vol. 
115
 
6
(pg. 
1247
-
1253
)