RESUMO
Extracellular vesicles derived from trophoblasts (T-EVs) play an important role in pregnancy, but the mechanism is not entirely clear. In this study, we found that HLA-E, which is mostly confined to the cytoplasm of trophoblast cells, was secreted by T-EVs. The level of HLA-E in T-EVs from unexplained recurrent spontaneous abortion (URSA) patients was lower than that in normal pregnancy (NP) and RSA patients who had an abnormal embryo karyotype (AK-RSA). T-EVs promoted secretion of IFN-γ and VEGFα by decidual NK (dNK) cells from URSA patients via HLA-E, VEGFα was necessary for angiogenesis and trophoblast growth, and IFN-γ inhibited Th17 induction. Glycolysis and oxidative phosphorylation (OxPhos) were involved in this process. Glycolysis but not OxPhos of dNK cells facilitated by T-EVs was dependent on mTORC1 activation. Inhibition of T-EV production in vivo increased the susceptibility of mice to embryo absorption, which was reversed by transferring exogenous T-EVs. T-EVs promoted secretion of IFN-γ and VEGFα by dNK cells to maintain pregnancy via Qa-1 in abortion-prone mouse models. This study reveals a new mechanism of pregnancy maintenance mediated by HLA-E via T-EVs.
Assuntos
Decídua/citologia , Vesículas Extracelulares/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais/fisiologia , Trofoblastos/fisiologia , Animais , Linhagem Celular , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Camundongos , Camundongos Nus , Placenta/citologia , Gravidez , Técnicas de Cultura de Tecidos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Antígenos HLA-ERESUMO
Postmenopausal women taking estrogen supplements are at a lower risk of advanced colorectal cancer, but the underlying mechanism remains unclear. Thus, this study examined the role of estrogen in colorectal cancer. Estrogen receptor expression levels in in situ colorectal cancer tissue from female patients increased significantly, indicating their estrogen sensitivity. Compared with the sham-operated group, the growth of MC38 tumors was enhanced in ovariectomized mice, which was reversed in ovariectomized mice with E2 supplementation. The PD-L1+ M2-like macrophage, regulatory T (Treg) cell, and myeloid-derived suppressor cell (MDSC) populations significantly increased, and the population of cytotoxic CD8+ T cells declined in MC38 tumors in ovariectomized mice, which were all reversed in ovariectomized mice with E2 supplementation. MC38 cell-derived extracellular vesicles (MC38-EVs), but not EVs derived from MC38 cells treated with E2 (E2-MC38-EVs), were involved in the establishment of immunosuppressive tumor microenvironment. E2-MC38-EVs contained lower TGF-ß1 levels and were less capable of inducing Treg cells than MC38-EVs in vitro. Overall, these results show that estrogen treatment prevents MC38 tumor growth via regulating the tumor immune microenvironment through MC38-EVs.
Assuntos
Neoplasias do Colo/metabolismo , Estrogênios/genética , Vesículas Extracelulares/imunologia , Fator de Crescimento Transformador beta1/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Estrogênios/metabolismo , Vesículas Extracelulares/genética , Feminino , Humanos , Terapia de Imunossupressão , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Objective: We explored the gut microbiome and serum metabolome alterations in patients with premature ovarian insufficiency (POI) and the effects of hormone replacement therapy (HRT) with the aim to unravel the pathological mechanism underlying POI. Methods: Fecal and serum samples obtained from healthy females (HC, n = 10) and patients with POI treated with (n = 10) or without (n = 10) HRT were analyzed using 16S rRNA gene sequencing and untargeted metabolomics analysis, respectively. Peripheral blood samples were collected to detect serum hormone and cytokine levels. Spearman's rank correlation was used to evaluate correlations between sex hormones and cytokines and between the gut microbiota and serum metabolites. To further confirm the correlation between Eggerthella and ovarian fibrosis, the mice were inoculated with Eggerthella lenta (E. lenta) through oral gavage. Results: The abundance of genus Eggerthella significantly increased in the fecal samples of patients with POI compared to that observed in the samples of HCs. This increase was reversed in patients with POI treated with HRT. Patients with POI showed significantly altered serum metabolic signatures and increased serum TGF-ß1 levels; this increase was reversed by HRT. The abundance of Eggerthella was positively correlated with altered metabolic signatures, which were, in turn, positively correlated with serum TGF-ß1 levels in all subjects. Estrogen ameliorated ovarian fibrosis induced by E. lenta in mice. Conclusions: The interactions between the gut microbiota, serum metabolites, and serum TGF-ß1 in patients with POI may play a critical role in the development of POI. HRT not only closely mimicked normal ovarian hormone production in patients with POI but also attenuated gut microbiota dysbiosis and imbalance in the levels of serum metabolites and TGF-ß1, which are reportedly associated with fibrosis. The findings of this study may pave the way for the development of preventive and curative therapies for patients with POI.
