17β-Oestradiol enhances the expansion and activation of myeloid-derived suppressor cells via signal transducer and activator of transcription (STAT)−3 signalling in human pregnancy

Abstract

1These authors contributed equally to this work. SummaryDuring a successful pregnancy, the maternal immune system plays a critical role in maintaining immunotolerance towards semi-allogeneic fetal antigens. Recent studies have indicated that myeloid-derived suppressor cells (MDSCs) are active players in establishing fetal-maternal tolerance; however, the underlying mechanism remains poorly understood. In this study, we observed a significant expansion of monocytic MDSCs (MMDSCs) in the peripheral blood of pregnant women, which suppressed T cell responses in a reactive oxygen species-dependent manner and required cell-cell contact. The number of M-MDSCs correlated positively with serum oestrogen and progesterone levels. Administration of 17b-oestradiol, but not progesterone, enhanced both the expansion and suppressive activity of M-MDSCs through signal transducer and activator of transcription (STAT)-3. Pretreatment with STAT-3 inhibitor JSI-124 almost completely abrogated the effects of 17b-oestradiol on MDSCs. Collectively, these results demonstrate that 17b-oestradiol-induced STAT-3 signalling plays an important role in both the expansion and activation of MDSCs during human pregnancy, which may benefit the development of novel therapeutic strategies for prevention of immune-related miscarriage.

HLA‐G promotes myeloid‐derived suppressor cell accumulation and suppressive activity during human pregnancy through engagement of the receptor ILT4

“…STAT3 has been described as one of the main transcription factors regulating MDSC function and accumulation, with HLA-G promoting its activation [47,48]. In line with our results, the pregnancy-associated sex hormone 17β-Estradiol was recently shown to activate MDSCs via STAT3 [49], and MDSCs accumulate via STAT3 due to its inhibition of their differentiation to dendritic cells (DCs) [31,50]. The exact mechanisms that lead to MDSCinduction via HLA-G will be subject of further studies.…”

Tumor Cell–Independent Estrogen Signaling Drives Disease Progression through Mobilization of Myeloid-Derived Suppressor Cells

“…Therefore, estrogenic activity prepares the bone marrow for acute expansion of myeloid precursors, but estrogen-dependent mobilization of MDSCs only occurs in the presence of direct inflammatory signals that activate JAK kinases, which may not necessarily be present during the high estrogen phase of the menstrual cycle. These mechanisms appear to be important during pregnancy though, where E2 also drives the expansion and activation of MDSCs (21), but our study demonstrates their relevance in the pathogenesis of women's malignancies.…”

“…In ovarian cancer, deregulated myelopoiesis results in the mobilization of myeloid-derived suppressor cells (MDSCs) from the bone marrow (15) and, eventually, the accumulation of tumor-promoting inflammatory Dendritic Cells (DCs) with immunosuppressive activity in solid tumors (16, 17), while canonical macrophages buildup in tumor ascites (16, 18). Although all these cell types express at least ERα and are influenced by estrogen signaling (19-21), how estrogens impact the orchestration and maintenance of protective anti-tumor immunity remains elusive. Here, we show that estrogens, independently of the sensitivity of tumor cells to estrogen signaling, are a crucial mechanism underlying pathological myelopoiesis in ovarian cancer.…”

Jianpi Huayu Decoction Attenuates the Immunosuppressive Status of H22 Hepatocellular Carcinoma-Bearing Mice: By Targeting Myeloid-Derived Suppressor Cells

“…NF-kB (Flores et al, 2017), STAT-3 (Guha et al, 2019), HMGB1, AMPK (Salminen et al, 2019), microRNAs (Ren et al, 2019). However, we suspected that JHD plays multiple roles by regulating STAT-3, which was involved in processes such as cell transformation, expansion and activation of MDSCs (Panni et al, 2014;Pan et al, 2016). Here, we have not yet studied the specific signaling pathways of above effect made by JHD, and based on our results, subsequent researches will be continued to explore definitely functional molecules and signaling pathways involved, to provide evidence for broadening the application of JHD.…”