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A balance between pro-inflammatory decidual CD4+ T cells and FOXP3+ regulatory T cells (FOXP3+ Tregs) is important for maintaining fetomaternal tolerance. Using single-cell RNA-sequencing and T cell receptor repertoire analysis, we determined that diversity and clonality of decidual CD4+ T cell subsets depend on gestational age. Th1/Th2 intermediate and Th1 subsets of CD4+ T cells were clonally expanded in both early and late gestation, whereas FOXP3+ Tregs were clonally expanded in late gestation. Th1/Th2 intermediate and FOXP3+ Treg subsets showed altered gene expression in preeclampsia (PE) compared to healthy late gestation. The Th1/Th2 intermediate subset exhibited elevated levels of cytotoxicity-related gene expression in PE. Moreover, increased Treg exhaustion was observed in the PE group, and FOXP3+ Treg subcluster analysis revealed that the effector Treg like subset drove the Treg exhaustion signatures in PE. The Th1/Th2 intermediate and effector Treg like subsets are possible inflammation-driving subsets in PE.
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Factores de Transcripción Forkhead , Edad Gestacional , Preeclampsia , Análisis de la Célula Individual , Linfocitos T Reguladores , Humanos , Femenino , Preeclampsia/inmunología , Preeclampsia/genética , Embarazo , Análisis de la Célula Individual/métodos , Adulto , Linfocitos T Reguladores/inmunología , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Linfocitos T CD4-Positivos/inmunología , Análisis de Secuencia de ARN , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células TH1/inmunología , Decidua/inmunologíaRESUMEN
Autophagy is a bulk degradation system that maintains cellular homeostasis by producing energy and/or recycling excess proteins. During early placentation, extravillous trophoblasts invade the decidua and uterine myometrium, facing maternal immune cells, which participate in the immune suppression of paternal and fetal antigens. Regulatory T cells will likely increase in response to a specific antigen before and during early pregnancy. Insufficient expansion of antigen-specific Treg cells, which possess the same T cell receptor, is associated with the pathophysiology of preeclampsia, suggesting sterile systemic inflammation. Autophagy is involved in reducing inflammation through the degradation of inflammasomes and in the differentiation and function of regulatory T cells. Autophagy dysregulation induces protein aggregation in trophoblasts, resulting in placental dysfunction. In this review, we discuss the role of regulatory T cells in normal pregnancies. In addition, we discuss the association between autophagy and regulatory T cells in the development of preeclampsia based on reports on the role of autophagy in autoimmune diseases.
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Placenta , Preeclampsia , Embarazo , Femenino , Humanos , Placenta/metabolismo , Placentación , Trofoblastos/fisiología , Autofagia , Inflamación/metabolismo , DeciduaRESUMEN
Autophagy is a fundamental process involved in regulating cellular homeostasis. Autophagy has been classically discovered as a cellular process that degrades cytoplasmic components non-selectively to produce energy. Over the past few decades, this process has been shown to work in energy production, as well as in the reduction of excessive proteins, damaged organelles, and membrane trafficking. It contributes to many human diseases, such as neurodegenerative diseases, carcinogenesis, diabetes mellitus, development, longevity, and reproduction. In this review, we provide important information for interpreting results related to autophagic experiments and present the role of autophagy in this field.
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Paternal antigen-specific regulatory T (PA-Treg) cells suppress the immune response against the fetus. Naturally occurring Treg (nTreg) cells derived from the thymus and peripherally induced Treg (iTreg) cells are functional for sustaining pregnancy. This study aimed to compare the variation in PA-Treg cells between the feto-maternal interface and the spleen and to elucidate the dynamics of nTreg and iTreg cells during the gestational period. PA-Treg cells, defined as Treg cells with paternally derived Mls-1a antigen-specific T cell receptors Vß6, from allogeneic pregnant mice on days 3.5, 5.5, 11.5, and 18.5 post-coitum (pc) were evaluated by flow cytometry. The percentage of Vß6+ Ki67+ PA-Treg cells activated by the paternal antigen increased on day 11.5 pc in the decidua (p < 0.05) compared to non-pregnant mice. On day 18.5 pc, this percentage in the decidua parietalis decreased to the level of the non-pregnant state but was significantly higher (p < 0.05) in the decidua basalis. No changes were observed in the spleens. We used two nTreg cell markers, neuropilin1 (Nrp1) and Helios, to distinguish between nTreg cells and iTreg cells. Nrp1+ PA-Treg cell levels decreased in late pregnancy compared to those observed in early pregnancy (day 3.5 pc: 57.14 ± 6.16% vs. day 18.5 pc: 30.43 ± 3.09%; p < 0.05), whereas Helios+ cell levels did not change. In conclusion, PA immune tolerance is induced by Nrp1+ nTreg cells in early pregnancy and Nrp1-negative Treg cells in late pregnancy.
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Bazo , Linfocitos T Reguladores , Femenino , Embarazo , Ratones , Animales , Neuropilina-1 , Útero , Timo , Factores de Transcripción ForkheadRESUMEN
Inhibition of autophagy contributes to the pathophysiology of preeclampsia. Although chloroquine (CHQ) is an autophagy inhibitor, it can reduce the occurrence of preeclampsia in women with systemic lupus erythematosus. To clarify this important clinical question, this study aimed to address the safety of CHQ in trophoblast cells from the viewpoint of homeostasis, in which the anti-oxidative stress (OS) response and autophagy are involved. We used Western blotting to evaluate the protein levels in the trophoblast cells. The expression levels of heme oxygenase-1 (HO-1), an anti-OS enzyme, mediate resistance to OS induced by hydrogen peroxide (H2O2) in trophoblast cell lines. Among the autophagy modulators, bafilomycin A1 (BAF), an autophagy inhibitor, but not autophagy activators, suppressed HO-1 expression in BeWo cells; CHQ did not suppress HO-1 expression in BeWo cells. To clarify the role of autophagy in HO-1 induction, we observed no difference in HO-1 induction by H2O2 between autophagy-normal and autophagy-deficient cells. As for the mechanism of HO-1 induction by OS, BAF suppressed HO-1 induction by downregulating the expression of neighbor of BRCA1 gene 1 (NBR1) in the selective p62-NBR1-nuclear factor erythroid 2-related factor 2 (Nrf2) autophagy pathway. CHQ did not inhibit HO-1 expression by sustaining NBR1 expression in human villous tissues compared to BAF treatment. In conclusion, CHQ is a safer medicine than BAF for sustaining NBR1, which resist against OS in trophoblasts by connecting selective autophagy and the anti-OS response.
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Antioxidantes , Preeclampsia , Embarazo , Humanos , Femenino , Antioxidantes/metabolismo , Antioxidantes/farmacología , Trofoblastos/metabolismo , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/farmacología , Cloroquina/farmacología , Cloroquina/metabolismo , Preeclampsia/tratamiento farmacológico , Preeclampsia/metabolismo , Transducción de Señal , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismoRESUMEN
Opportunities for the exposure of pregnant women to engineered nanoparticles have been increasing with the expanding use of these materials. Therefore, there are concerns that nanoparticles could have adverse effects on the establishment and maintenance of pregnancy. The effects of nanoparticles on the mother and fetus have been evaluated from this perspective, but there is still little knowledge about the effects on placentation and function acquisition, which are essential for the successful establishment and maintenance of pregnancy. Formation of the syncytiotrophoblast is indispensable for the acquisition of placental function, and impairment of syncytialization inevitably affects pregnancy outcomes. Here, we assessed the effect of nanoparticles on placental formation by using forskolin-treated BeWo cells, a typical in vitro model of trophoblast syncytialization. Immunofluorescence staining analysis revealed that silver nanoparticles with a diameter of 10 nm (nAg10) (at 0.156 µg/mL) significantly decreased the proportion of syncytialized BeWo cells, but gold nanoparticles with a diameter of 10 nm did not. Consistently, only nAg10 (at 0.156 µg/mL) significantly suppressed forskolin-induced elevation of CGB and SDC1 mRNA expression levels and human chorionic gonadotropin ß production in a dose-dependent manner; these molecules are all markers of syncytialization. Besides, nAg10 significantly decreased the expression of ERVFRD-1, which encodes proteins associated with cell fusion. Moreover, nAg10 tended to suppress the expression of sFlt-1 e15a, a placental angiogenesis marker. Collectively, our data suggest that nAg10 could suppress formation of the syncytiotrophoblast and that induce placental dysfunction and the following poor pregnancy outcomes.
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Nanopartículas del Metal , Placenta , Femenino , Embarazo , Humanos , Colforsina/farmacología , Plata , OroRESUMEN
Aggrephagy is defined as the selective degradation of aggregated proteins by autophagosomes. Protein aggregation in organs and cells has been highlighted as a cause of multiple diseases, including neurodegenerative diseases, cardiac failure, and renal failure. Aggregates could pose a hazard for cell survival. Cells exhibit three main mechanisms against the accumulation of aggregates: protein refolding by upregulation of chaperones, reduction of protein overload by translational inhibition, and protein degradation by the ubiquitin-proteasome and autophagy-lysosome systems. Deletion of autophagy-related genes reportedly contributes to intracellular protein aggregation in vivo. Some proteins recognized in aggregates in preeclamptic placentas include those involved in neurodegenerative diseases. As aggregates are derived both intracellularly and extracellularly, special endocytosis for extracellular aggregates also employs the autophagy machinery. In this review, we discuss how the deficiency of aggrephagy and/or macroautophagy leads to poor placentation, resulting in preeclampsia or fetal growth restriction.
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Macroautofagia , Placenta/fisiopatología , Preeclampsia/fisiopatología , Animales , Femenino , Humanos , Lisosomas/metabolismo , Placenta/metabolismo , Preeclampsia/etiología , Preeclampsia/metabolismo , Embarazo , Agregación Patológica de ProteínasRESUMEN
Cytotrophoblasts differentiate in two directions during early placentation: syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). STBs face maternal immune cells in placentas, and EVTs, which invade the decidua and uterine myometrium, face the cells in the uterus. This situation, in which trophoblasts come into contact with maternal immune cells, is known as the maternal-fetal interface. Despite fetuses and fetus-derived trophoblast cells being of the semi-allogeneic conceptus, fetuses and placentas are not rejected by the maternal immune system because of maternal-fetal tolerance. The acquired tolerance develops during normal placentation, resulting in normal fetal development in humans. In this review, we introduce placental development from the viewpoint of molecular biology. In addition, we discuss how the disruption of placental development could lead to complications in pregnancy, such as hypertensive disorder of pregnancy, fetal growth restriction, or miscarriage.
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Decidua/inmunología , Células Gigantes/inmunología , Placenta/inmunología , Embarazo/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autofagia , Femenino , Histocompatibilidad Materno-Fetal , Humanos , Tolerancia InmunológicaRESUMEN
PROBLEM: Pre-ovulatory mature follicles are not readily induced from gonadotropin (Gn)-independent early follicles in the poor ovarian response (POR) state, characterized by reduced number of retrieved oocytes. Bone morphogenetic protein (BMP), which is expressed in the ovary, contributes to early folliculogenesis, but its precise underlying mechanism remains unknown. The purpose of this study was to examine the effects of BMP-2 on granulosa cells (GCs) of Gn-independent early follicles. METHOD OF STUDY: Sphingosine kinase 1 (SPHK1) localization, which produces sphingosine 1-phosphate (S1P), was examined in human early follicles by immunohistochemistry. SPHK1 mRNA levels were examined in Gn-independent bovine GCs (bGCs) and human nonluteinized granulosa cell line (HGrC1) cells. Phosphorylated Yes-associated protein (YAP) expression was evaluated by Western blot, and its localization was evaluated immunocytochemically in bGCs. Verteporfin, a selective YAP inhibitor, was used to explore the influence of YAP on BMP-2-induced bGCs proliferation. RESULTS: The expression of SPHK1 was observed in human GCs of primary and secondary follicles. BMP-2 significantly induced SPHK1 mRNA expression in bGCs and HGrC1 cells. Both BMP-2 and S1P decreased phosphorylated YAP protein levels and induced the nuclear translocation of YAP significantly, thereby increasing the number of bGCs by suppressing the Hippo pathway. This BMP-2-induced cell proliferation was completely blocked by verteporfin. CONCLUSION: This is a first report showing that BMP-2 up-regulated SPHK1 mRNA expression in GCs and promoted GCs proliferation through Hippo pathway suppression. Thus, BMP-2 contributes to Gn-independent folliculogenesis via SPHK1, suggesting a potential therapeutic strategy for the POR patients with follicular dysgenesis.
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Proteína Morfogenética Ósea 2/metabolismo , Células de la Granulosa/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Bovinos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Gonadotropinas , Células de la Granulosa/efectos de los fármacos , Humanos , Lisofosfolípidos/farmacología , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Esfingosina/análogos & derivados , Esfingosina/farmacología , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAPRESUMEN
Macrophages (MΦs) play important roles in implantation. Depletion of CD11b+ pan-MΦs in CD11b-diphtheria-toxin-receptor (DTR) mice is reported to cause implantation failure due to decreased progesterone production in the corpus luteum. However, of the M1 and M2, the type of MΦs that is important for implantation is unknown. In this study, we investigated the role of M2 MΦ in implantation using CD206-DTR mice. To deplete M2-MΦ, female CD206-DTR C57/BL6 mice were injected with DT before implantation. These M2-MΦ depleted mice (M2(-)) were naturally mated with Balb/C mice. As the control group, female C57/BL6 wild type (WT) mice injected with DT were mated with male Balb/C mice. The number of implantation sites and plasma progesterone levels at implantation were examined. Implantation-related molecule expression was determined using quantitative-PCR and immunohistochemistry of uterine tissues. The mRNA expression in the endometrial tissues of 38 patients with implantation failure was examined during the implantation window. In WT mice, CD206+M2-like MΦs accumulated in the endometrium at the implantation period, on embryonic (E) 4.5. In M2(-), the implantation number was significantly lower than that in control (p < 0.001, 7.8 ± 0.8 vs. 0.2 ± 0.4), although the plasma progesterone levels were not changed. Leukemia inhibitory factor (LIF) and CD206 mRNA expression was significantly reduced (p < 0.01), whereas the levels of TNFα were increased on E4.5 (p < 0.05). In M2(-), the number of Ki-67+ epithelial cells was higher than that in control at the pre-implantation period. Accelerated epithelial cell proliferation was confirmed by significantly upregulated uterine fibroblast growth factor (FGF)18 mRNA (P < 0.05), and strong FGF18 protein expression in M2(-) endometrial epithelial cells. Further, M2(-) showed upregulated uterine Wnt/ß-catenin signals at the mRNA and protein levels. In the non-pregnant group, the proportion of M2-like MΦ to pan MΦ, CD206/CD68, was significantly reduced (p < 0.05) and the TNFα mRNA expression was significantly increased (p < 0.05) in the endometrial tissues compared to those in the pregnant group. CD206+ M2-like MΦs may be essential for embryo implantation through the regulation of endometrial proliferation via Wnt/ß-catenin signaling.
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Lectinas Tipo C/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Lectinas de Unión a Manosa/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Biomarcadores , Plasticidad de la Célula/inmunología , Proliferación Celular , Implantación del Embrión , Células Epiteliales/metabolismo , Femenino , Inmunohistoquímica , Infertilidad , Inflamación/etiología , Inflamación/metabolismo , Lectinas Tipo C/genética , Activación de Macrófagos/genética , Activación de Macrófagos/inmunología , Receptor de Manosa , Lectinas de Unión a Manosa/genética , Ratones , Receptores de Superficie Celular/genética , Útero , Vía de Señalización WntRESUMEN
Dendritic cells (DCs) are essential for successful embryo implantation. However, the properties of uterine DCs (uDCs) during the implantation period are not well characterized. In this study, we investigated the dynamic changes in the uDC phenotypes during the period between coitus and implantation. In virgin mice, we evaluated the expressions of CD103 and XCR1, this is the first report to demonstrate uDCs expressing CD103 in XCR1+cDC1s and XCR1+cDC2s. On day 0.5 post coitus (pc), the number of uterine CD11c+CD103-MHC classIIhighCD86high-mature DCs rapidly increased and then decreased to non-pregnancy levels on days 1.5 and 2.5 pc. On day 3.5 pc just before implantation, the number of CD11c+CD103+MHC class IIdimCD86dim-immature DCs increased in the uterus. The increase in mature uDCs on day 1.5 pc was observed in both allogeneic- and syngeneic mating, suggesting that sexual intercourse, or semen, play a role in this process. Meanwhile, the increase in immature uDCs on day 3.5 pc was only observed in allogeneic mating, suggesting that allo-antigens in the semen contribute to this process. Next, to understand the turnover and migration of uDCs, we monitored DC movement in the uterus and uterine draining lymph nodes (dLNs) using photoconvertible protein Kikume Green Red (KikGR) mice. On day 0.5 pc, uDCs were composed of equal numbers of remaining DCs and migratory DCs. However, on day 3.5 pc, uDCs were primarily composed of migratory DCs, suggesting that most of the uDCs migrate from the periphery just before implantation. Finally, we studied the expression of PD-L2-which induces immunoregulation-on DCs. On day 3.5 pc, PD-L2 was expressed on CD103+-mature and CD103--mature DCs in the uterus. However, PD-L2 expression on CD103--immature DCs and CD103+-immature DCs was very low. Furthermore, both remaining and migratory DCs in the uterus and uterus-derived-DCs in the dLNs on day 3.5 pc highly expressed PD-L2 on their surface. Therefore, our study findings provide a better understanding of the dynamic changes occurring in uterine DCs and dLNs in preparation for implantation following allogeneic- and syngeneic mating.
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Coito/fisiología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Fenotipo , Útero/fisiología , Animales , Biomarcadores , Diferenciación Celular/inmunología , Plasticidad de la Célula/inmunología , Implantación del Embrión/genética , Implantación del Embrión/inmunología , Femenino , Inmunofenotipificación , RatonesRESUMEN
Hypertensive disorders of pregnancy, including preeclampsia, directly affect maternal and perinatal morbidity and mortality. As the pathophysiology of preeclampsia is multi-factorial and has been studied using different approaches, we have demonstrated that impaired autophagy is an intertwined risk factor for preeclampsia. This concept has been verified in both in vitro and in vivo experiments. Autophagy is primarily involved in maintaining cellular homeostasis, and in immune regulation, longevity, cytokines secretion and a variety of other biological functions. Here, we review the role of autophagy in normal embryogenesis and placentation. Once placental autophagy is impaired by metabolic stress such as hypoxia, endoplasmic reticulum stress or starvation, placental development could be disrupted, resulting in functional maladaptations at the maternal-fetal interface. These malfunctions may result in fetal growth restriction or preeclampsia.
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CD8+ T cells, the most abundant T cell subset in the decidua, play a critical role in the maintenance of pregnancy. The majority of decidual CD8+ T cells have an effector memory phenotype, while those in the peripheral blood display a naive phenotype. An increased amount of highly differentiated CD8+ T cells in the decidua indicates local antigen stimulation and expansion, albeit these CD8+ T cells are suppressed. In decidual CD8+ T cells, co-inhibitory molecules such as PD-1, TIM-3, LAG-3, and CTLA-4 are upregulated, reflecting the suppression of cytotoxicity. Previous studies established the importance of the PD-1/PD-L1 interaction for feto-maternal tolerance. CD8+ T cells could directly recognize fetal-specific antigens, such as HLA-C, expressed by trophoblasts. However, although fetal-specific CD8+ T cells have been reported, their TCR repertoires have not been identified. In this study, we analyzed the TCR repertoires of effector memory CD8+ T cells (CD8+ EM cells) and naive CD8+ T cells (CD8+ N cells) in the decidua and peripheral blood of women with normal or complicated pregnancy and examined PD-1 expression at a single-cell level to verify whether antigen-specific CD8+ T cells accumulate in the decidua and to identify immunological differences related to the suppression of antigen-specific CD8+ T cells between normal pregnancy, miscarriage, and preeclampsia. We observed that some TCRß repertoires, which might recognize fetal or placental antigens, were clonally expanded. The population size of clonally expanded CD8+ EM cells was higher in the decidua than in the peripheral blood. CD8+ EM cells began to express PD-1 during the course of normal pregnancy. We found that the total proportion of decidual CD8+ EM cells not expressing PD-1 was increased both in miscarriage and in preeclampsia cases, although a different mechanism was responsible for this increase. The amount of cytotoxic CD8+ EM cells increased in cases of miscarriage, whereas the expression of PD-1 in clonally expanded CD8+ EM cells was downregulated in preeclampsia cases. These results demonstrated that decidual CD8+ EM cells were able to recognize fetal-specific antigens at the feto-maternal interface and could easily induce fetal rejection.
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Aborto Espontáneo/inmunología , Linfocitos T CD8-positivos/inmunología , Preeclampsia/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Aborto Espontáneo/sangre , Aborto Espontáneo/genética , Adulto , Estudios de Casos y Controles , Células Clonales/inmunología , Decidua/inmunología , Femenino , Histocompatibilidad Materno-Fetal/genética , Histocompatibilidad Materno-Fetal/inmunología , Humanos , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Inmunofenotipificación , Preeclampsia/sangre , Preeclampsia/genética , Embarazo , Receptor de Muerte Celular Programada 1/genética , Receptores de Antígenos de Linfocitos T/genética , Adulto JovenRESUMEN
Tolerogenic dendritic cells (tDCs) play a central role in the development of paternal antigen-specific regulatory T cells (Tregs) during pregnancy. We examined whether uterine CD11c+ antigen presenting cells (APC) induced paternal antigen-specific tolerance in allogeneic pregnant mice. Female BALB/c mice were mated with male DBA/2 mice, and their surface markers of APCs were studied using flow cytometry. After allogeneic mating, the uterine APCs exhibited significantly decreased expression of major histocompatibility complex (MHC) class II on day 3.5 post-coitus (pc) and day 5.5 pc. To analyze how seminal fluid affects surface markers of APCs, female BALB/c mice were mated with male mice that had undergone seminal vesicle excision (SVX). No reductions of MHC class II expression on APCs were seen in these mice. To analyze APC functions, a mixed lymphoid reaction (MLR) assay to paternal splenocytes was performed. Uterine APCs from allogeneic pregnant mice significantly suppressed the MLR reaction, but APCs from SVX mated mice did not suppress the MLR reaction Uterine APCs induced paternal antigen (Mls1a)-specific Treg development in vitro, but not in mice that mated with allogeneic SVX mice. These findings suggest that seminal fluid priming expands the paternal antigen-specific Treg population by inducing APCs development.
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Células Dendríticas/inmunología , Tolerancia Inmunológica , Semen/inmunología , Linfocitos T Reguladores/inmunología , Útero/inmunología , Animales , Presentación de Antígeno , Antígenos CD11/metabolismo , Comunicación Celular/inmunología , Células Cultivadas , Células Dendríticas/metabolismo , Femenino , Antígenos H-2/inmunología , Antígenos H-2/metabolismo , Isoantígenos/inmunología , Isoantígenos/metabolismo , Masculino , Ratones , Modelos Animales , Embarazo , Semen/metabolismo , Linfocitos T Reguladores/metabolismo , Útero/citologíaRESUMEN
Placental homeostasis is directly linked to fetal well-being and normal fetal growth. Placentas are sensitive to various environmental stressors, including hypoxia, endoplasmic reticulum stress, and oxidative stress. Once placental homeostasis is disrupted, the placenta may rebel against the mother and fetus. Autophagy is an evolutionally conservative mechanism for the maintenance of cellular and organic homeostasis. Evidence suggests that autophagy plays a crucial role throughout pregnancy, including fertilization, placentation, and delivery in human and mouse models. This study reviews the available literature discussing the role of autophagy in preeclampsia.
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Placenta/fisiopatología , Preeclampsia/fisiopatología , Autofagia , Estrés del Retículo Endoplásmico , Femenino , Homeostasis , Humanos , Estrés Oxidativo , Placenta/metabolismo , Preeclampsia/metabolismo , Embarazo , Transducción de SeñalRESUMEN
Pregnancy is a stress factor culminating into mild endoplasmic reticulum (ER) stress, which is necessary for placental development. However, excessive or chronic ER stress in pre-eclamptic placentas leads to placental dysfunction. The precise mechanisms through which excessive ER stress impacts trophoblasts are not well understood. Here, we showed that ER stress reduces the number of lysosomes, resulting in inhibition of autophagic flux in trophoblast cells. ER stress also disrupted the translocation of lysosomes to the surface of trophoblast cells, and inhibited lysosomal exocytosis, whereby the secretion of lysosomal-associated membrane protein 1 (LAMP1) into culture media was significantly attenuated. In addition, we found that serum LAMP1 and beta-galactosidase levels were significantly decreased in pre-eclampsia patients compared to normal pregnant women, potentially indicating lysosomal dysfunction through ER stress in pre-eclamptic placentas. Thus, we demonstrated that excessive ER stress essentially disrupts homeostasis in trophoblasts in conjunction with autophagy inhibition by lysosomal impairment.
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Autofagia , Estrés del Retículo Endoplásmico , Lisosomas/patología , Preeclampsia/patología , Trofoblastos/patología , Adulto , Biomarcadores/sangre , Biomarcadores/metabolismo , Línea Celular , Medios de Cultivo/metabolismo , Exocitosis , Femenino , Humanos , Proteínas de Membrana de los Lisosomas/sangre , Proteínas de Membrana de los Lisosomas/metabolismo , Lisosomas/metabolismo , Placentación , Preeclampsia/sangre , Preeclampsia/diagnóstico , Embarazo , Cultivo Primario de Células , Trofoblastos/citología , beta-Galactosidasa/sangre , beta-Galactosidasa/metabolismoRESUMEN
Autophagy is an evolutionarily conserved process in eukaryotes to maintain cellular homeostasis under environmental stress. Intracellular control is exerted to produce energy or maintain intracellular protein quality controls. Autophagy plays an important role in embryogenesis, implantation, and maintenance of pregnancy. This role includes supporting extravillous trophoblasts (EVTs) that invade the decidua (endometrium) until the first third of uterine myometrium and migrate along the lumina of spiral arterioles under hypoxic and low-nutrient conditions in early pregnancy. In addition, autophagy inhibition has been linked to poor placentation-a feature of preeclamptic placentas-in a placenta-specific autophagy knockout mouse model. Studies of autophagy in human placentas have revealed controversial results, especially with regard to preeclampsia and gestational diabetes mellitus (GDM). Without precise estimation of autophagy flux, wrong interpretation would lead to fixed tissues. This paper presents a review of the role of autophagy in pregnancy and elaborates on the interpretation of autophagy in human placental tissues.
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Autofagia , Animales , Autofagia/genética , Femenino , Humanos , Modelos Biológicos , Placentación , Embarazo , Complicaciones del Embarazo/patología , ReproducciónRESUMEN
Nanoparticles are widely used in commodities, and pregnant women are inevitably exposed to these particles. The placenta protects the growing fetus from foreign or toxic materials, and provides energy and oxygen. Here we report that autophagy, a cellular mechanism to maintain homeostasis, engulfs platinum nanoparticles (nPt) to reduce their cytotoxicity in trophoblasts. Autophagy was activated by nPt in extravillous trophoblast (EVT) cell lines, and EVT functions, such as invasion and vascular remodeling, and proliferation were inhibited by nPt. These inhibitory effects by nPt were augmented in autophagy-deficient cells. Regarding the dynamic state of nPt, analysis using ICP-MS demonstrated a higher accumulation of nPt in the autophagosome-rich than the cytoplasmic fraction in autophagy-normal cells. Meanwhile, there were more nPt in the nuclei of autophagy-deficient cells, resulting in greater DNA damage at a lower concentration of nPt. Thus, we found a new protective mechanism against the cytotoxicity of nPt in human trophoblasts.
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Proteínas Relacionadas con la Autofagia/metabolismo , Platino (Metal)/toxicidad , Trofoblastos/citología , Remodelación Vascular/efectos de los fármacos , Autofagia , Proteínas Relacionadas con la Autofagia/genética , Línea Celular , Movimiento Celular/efectos de los fármacos , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Citoplasma/genética , Citoplasma/metabolismo , Femenino , Humanos , Nanopartículas del Metal/toxicidad , Tamaño de la Partícula , Embarazo , Trofoblastos/efectos de los fármacos , Trofoblastos/metabolismoRESUMEN
PROBLEM: Premature ovarian insufficiency (POI) is a clinical syndrome defined by the loss of ovarian activity before 40 years old. An autoimmune mechanism is suggested to be involved in the development of POI. Therefore, we examined the relationship between peripheral blood regulatory T (Treg) cells and autoantibodies in POI. METHOD OF STUDY: Thirty POI patients and 23 control women were enrolled in the study. Using flow cytometry, we measured the abundance of CD4+ T, CD4+ CD69+ T, CD8+ T, CD8+ CD69+ T, naive Treg, effector Treg, and FOXP3+ effector T cells in peripheral blood. Antinuclear and anti-thyroglobulin antibody (Tg-Ab) titers were measured in POI patients. RESULTS: The number of CD4+ T or CD4+ CD69+ T cells was significantly higher in POI patients (P = 0.045, and P = 0.030), and there were significantly fewer effector Treg cells in POI patients (P = 0.016) than in the controls. There were significant negative correlations between effector Treg cells and Tg-Abs (r = -0.584, P = 0.0282), and between effector Treg cells and CD4+ CD69+ T cells (r = -0.415, P = 0.0226) in POI patients. CONCLUSION: This is the first report of decreased numbers of effector Treg cells and increased CD4+ CD69+ activated T cells in peripheral blood in POI, suggesting that POI is an autoimmune disease.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Insuficiencia Ovárica Primaria/inmunología , Adulto , Recuento de Linfocito CD4 , Femenino , HumanosRESUMEN
Background: Regulatory T (Treg) cells are necessary for the maintenance of allogenic pregnancy. However, the repertoire of effector Treg cells at the feto-maternal interface in human pregnancy remains unknown. Our objective was to study T cell receptor (TCR) repertoires of Treg cells during pregnancy compared to normal and complicated pregnancies. Methods:Paired samples of peripheral blood and decidua in induced abortion and miscarriage cases were obtained from consenting patients. CD4+CD25+CD127low/-CD45RA- effector Treg cells were single-cell sorted from mononuclear cells. cDNAs of complementarity determining region 3 (CDR3) in TCRß were amplified from the single cells by RT-PCR and the sequences were analyzed. The TCRß repertoires were determined by amino acid and nucleotide sequences. Treg cells were classified into clonally expanded and non-expanded populations by CDR3 sequences. Results: We enrolled nine induced abortion cases in the 1st trimester, 12 cases delivered without complications in the 3rd trimester, 11 miscarriages with abnormal chromosomal karyotyped embryo, seven miscarriages with normal chromosomal karyotyped embryo, and seven cases of preeclampsia [median gestational week (interquartile range): 7 (7-9), 39 (38-40), 9 (8-10), 8 (8-10), and 34 (32-37), respectively]. The frequency of clonally expanded populations of effector Treg cells increased in decidua of 3rd trimester cases compared to 1st trimester cases [4.5% (1.4-10.8%) vs. 20.9% (15.4-28.1%), p < 0.001]. Clonally expanded Treg cells were rarely seen in peripheral blood. The ratio of clonally expanded populations of decidual effector Treg cells in miscarriages with abnormal and normal embryos was not significantly different compared with that in 1st trimester normal pregnancy. Interestingly, clonally expanded populations of effector Treg cells decreased in preeclampsia compared with that in 3rd trimester normal pregnancy [9.3% (4.4-14.5%) vs. 20.9% (15.4-28.1%), p = 0.003]. When repertoires in previous pregnancy and subsequent pregnancy were compared, some portions of the repertoire were shared. Conclusion: TCR repertoires of decidual effector Treg cells are skewed in the 3rd trimester of normal pregnancy. Failure of clonal expansion of populations of decidual effector Treg cells might be related to the development of preeclampsia.