RESUMEN
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.
Asunto(s)
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
The etiology of preeclampsia (PE), a severe complication of pregnancy with several clinical manifestations and a high incidence of maternal and fetal morbidity and mortality, remains unclear. This issue is a major hurdle for effective treatment strategies. We recently demonstrated that PE exhibits an Alzheimer-like etiology of impaired autophagy and proteinopathy in the placenta. Targeting of these pathological pathways may be a novel therapeutic strategy for PE. Stimulation of autophagy with the natural disaccharide trehalose and its lacto analog lactotrehalose in hypoxia-exposed primary human trophoblasts restored autophagy, inhibited the accumulation of toxic protein aggregates, and restored the ultrastructural features of autophagosomes and autolysosomes. Importantly, trehalose and lactotrehalose inhibited the onset of PE-like features in a humanized mouse model by normalizing autophagy and inhibiting protein aggregation in the placenta. These disaccharides restored the autophagy-lysosomal biogenesis machinery by increasing nuclear translocation of the master transcriptional regulator TFEB. RNA-seq analysis of the placentas of mice with PE indicated the normalization of the PE-associated transcriptome profile in response to trehalose and lactotrehalose. In summary, our results provide a novel molecular rationale for impaired autophagy and proteinopathy in patients with PE and identify treatment with trehalose and its lacto analog as promising therapeutic options for this severe pregnancy complication.
Asunto(s)
Autofagia , Lisosomas , Preeclampsia , Trehalosa , Autofagia/efectos de los fármacos , Preeclampsia/tratamiento farmacológico , Preeclampsia/metabolismo , Femenino , Humanos , Embarazo , Animales , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Trehalosa/análogos & derivados , Trehalosa/farmacología , Trehalosa/uso terapéutico , Ratones , Trofoblastos/metabolismo , Trofoblastos/efectos de los fármacos , Trofoblastos/patología , Placenta/metabolismo , Placenta/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
Twelve years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 5th Revised Edition was published in 2023. The 2023 Guidelines includes 5 additional clinical questions (CQs), which brings the total to 103 CQ (12 on infectious disease, 30 on oncology and benign tumors, 29 on endocrinology and infertility and 32 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.
Asunto(s)
Ginecología , Obstetricia , Humanos , Japón , Femenino , Ginecología/normas , Obstetricia/normas , Sociedades Médicas/normas , Enfermedades de los Genitales Femeninos/diagnóstico , Enfermedades de los Genitales Femeninos/terapia , Obstetras , GinecólogosRESUMEN
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.
Asunto(s)
Placenta , Preeclampsia , Embarazo , Femenino , Humanos , Placenta/metabolismo , Placentación , Trofoblastos/fisiología , Autofagia , Inflamación/metabolismo , DeciduaRESUMEN
Our prior studies have shown that protein misfolding and aggregation in the placenta are linked to the development of preeclampsia, a severe pregnancy complication. We identified transthyretin (TTR) as a key component of the aggregated protein complex. However, the regulation of native TTR in normal pregnancy remains unclear. In this study, we found that pregnant mice exhibited a remarkable and progressive decline in serum TTR levels through gestational day (gd) 12-14, followed by an increase in late pregnancy and postpartum. Meanwhile, serum albumin levels showed a modest but statistically significant increase throughout gestation. TTR protein and mRNA levels in the liver, a primary source of circulating TTR, mirrored the changes observed in serum TTR levels during gestation. Intriguingly, a similar pattern of TTR alteration was also observed in the serum of pregnant women and pregnant interleukin-10-knockout (IL-10-/-) mice with high inflammation background. In non-pregnant IL-10-/- mice, serum TTR levels were significantly lower than those in age-matched wild-type mice. Administration of IL-10 to non-pregnant IL-10-/- mice restored their serum TTR levels. Notably, dysregulation of TTR resulted in fewer implantation units, lower fetal weight, and smaller litter sizes in human TTR-overexpressing transgenic mice. Thus, TTR may play a pivotal role as a crucial regulator in normal pregnancy, and inflammation during pregnancy may contribute to the downregulation of serum TTR presence.
RESUMEN
Preeclampsia is more common in nulliparous women, their first pregnancies with a new partner in multiparous women, pregnant women with short duration of cohabitation, and in pregnancies with donor eggs, where the fetus is completely foreign to the mother. The epidemiological study findings strongly suggest that inadequate induction of tolerance to paternal/fetal antigens is involved in the pathogenesis of preeclampsia. This review proposes that preeclampsia may be caused by a reduction in paternal/fetal antigen-specific regulatory T (Treg) cells and decreased PD-1 expression on clonally expanded CD8+ effector memory T (TEM) cells, resulting in a breakdown of mother-to-fetus tolerance. The immune environment of preeclampsia is clearly different from that of recurrent pregnancy loss (RPL). In preeclampsia, cloned Treg cells decreases, and PD-1 expression on cloned CD8+TEM decreased. In RPL, the total number of Treg cells decreased, and the total number of clonally expanded CD8+TEM cells increases. In addition to these changes, increased differentiation of Th17 cells has also been observed in preeclampsia. This change is caused by soluble endoglin, that is increased in preeclampsia, neutralizing TGFß. These immunological changes make the fetus more susceptible to attacks from maternal T cells.
Asunto(s)
Aborto Habitual , Preeclampsia , Femenino , Humanos , Embarazo , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T Reguladores , Antígenos/metabolismo , Tolerancia Inmunológica , Aborto Habitual/patologíaRESUMEN
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.
RESUMEN
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.
Asunto(s)
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.
Asunto(s)
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
We have previously described that placental activation of autophagy is a central feature of normal pregnancy, whereas autophagy is impaired in preeclampsia (PE). Here, we show that hypoxia-reoxygenation (H/R) treatment dysregulates key molecules that maintain autophagy-lysosomal flux in primary human trophoblasts (PHTs). Ultrastructural analysis using transmission electron microscopy reveals a significant reduction in autophagosomes and autolysosomes in H/R-exposed PHTs. H/R-induced accumulation of protein aggregates follows a similar pattern that occurs in PHTs treated with a lysosomal disruptor, chloroquine. Importantly, the placenta from early-onset PE deliveries exhibits the same features as seen in H/R-treated PHTs. Taken together, our results indicate that H/R disrupts autophagic machinery in PHTs and that impaired autophagy in the placenta from early-onset PE deliveries mimics the events in H/R-treated PHTs. Notably, assessment of key regulators at each stage of autophagic processes, especially lysosomal integrity, and verification of autophagic ultrastructure are essential for an accurate evaluation of autophagy activity in human trophoblasts and placental tissue from PE deliveries.
Asunto(s)
Preeclampsia , Trofoblastos , Autofagia/fisiología , Femenino , Humanos , Hipoxia/metabolismo , Lisosomas/metabolismo , Placenta/metabolismo , Preeclampsia/metabolismo , Embarazo , Trofoblastos/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.
Asunto(s)
Nanopartículas del Metal , Placenta , Femenino , Embarazo , Humanos , Colforsina/farmacología , Plata , OroRESUMEN
Dysprothrombinemia is the rarest inherited bleeding disorder that is characterized by a decrease in the prothrombin activity, but normal antigen levels. In this study, we report the case of a compound heterozygote of two mutations in prothrombin; Met337Thr and Arg388His, which has previously been identified as "Prothrombin Himi." A systemic blood coagulation evaluation revealed a prolonged prothrombin time (39%) and activated partial thromboplastin (64.4 sec), with an isolated severe decrease in the prothrombin activity (8.6%). Preoperative replacement of prothrombin with prothrombin complex concentrate, PPSB-HT "Nichiyaku," successfully prevented abnormal postoperative bleeding after laparoscopic hysterectomy for cervical cancer. This is the second reported case of Prothrombin Himi.
Asunto(s)
Protrombina , Factores de Coagulación Sanguínea , HumanosRESUMEN
Understanding of sterile inflammation and its associated biological triggers and diseases is still at the elementary stage. This becomes more warranted in cases where infections are not associated with the pathology. Detrimental effects of bacterial and viral infections on the immune responses at the maternal-fetal interface as well as pregnancy outcomes have been well documented. However, an infection-induced etiology is not thought to be a major contributing component to severe pregnancy complications such as preeclampsia (PE) and gestational diabetes. How is then an inflammatory signal thought to be associated with these pregnancy complications? It is not clear what type of inflammation is involved in the onset of PE-like features. We opine that sterile inflammation regulated by the inflammasome-gasdermins-caspase-1 axis is a contributory factor to the onset of PE. We hypothesize that increased production and release of damage-associated molecular patterns (DAMPs) or Alarmins such as high-mobility group box1 (HMGB1), cell-free fetal DNA, uric acid, the NOD-like receptor pyrin-containing receptor 3 (NLRP3) inflammasome, IL-1ß and IL-18 occur in the PE placenta. Some of these molecules have already been observed in the placenta from women with PE. Mechanistically, emerging evidence has demonstrated that excessive placental endoplasmic reticulum (ER) stress, impaired autophagy and gasdermine D (GSDMD)-mediated intrinsic pyroptosis are key events that contribute to systemic sterile inflammation in patients with PE, especially early-onset PE (e-PE). In this review, we highlight the advances on the roles of sterile inflammation and inflammatory signaling cascades involving ER stress, autophagy deficiency and pyroptosis in PE pathophysiology. Deciphering the mechanisms underlying these inflammatory pathways may provide potential diagnostic biomarkers and facilitate the development of therapeutic strategies to treat this devastating disease.
Asunto(s)
Preeclampsia , Femenino , Humanos , Inflamasomas , Inflamación , Proteína con Dominio Pirina 3 de la Familia NLR , Placenta , Preeclampsia/etiología , EmbarazoRESUMEN
A non-invasive and sensitive blood test has long been a goal for early stage disease diagnosis and treatment for Alzheimer's disease (AD) and other proteinopathy diseases. We previously reported that preeclampsia (PE), a severe pregnancy complication, is another proteinopathy disorder with impaired autophagy. We hypothesized that induced autophagy deficiency would promote accumulation of pathologic protein aggregates. Here, we describe a novel, sensitive assay that detects serum protein aggregates from patients with PE (n = 33 early onset and 33 late onset) and gestational age-matched controls (n = 77) as well as AD in both dementia and prodromal mild cognitive impairment (MCI, n = 24) stages with age-matched controls (n = 19). The assay employs exposure of genetically engineered, autophagy-deficient human trophoblasts (ADTs) to serum from patients. The aggregated protein complexes and their individual components, including transthyretin, amyloid ß-42, α-synuclein, and phosphorylated tau231, can be detected and quantified by co-staining with ProteoStat, a rotor dye with affinity to aggregated proteins, and respective antibodies. Detection of protein aggregates in ADTs was not dependent on transcriptional upregulation of these biomarkers. The ROC curve analysis validated the robustness of the assay for its specificity and sensitivity (PE; AUC: 1, CI: 0.949-1.00; AD; AUC: 0.986, CI: 0.832-1.00). In conclusion, we have developed a novel, noninvasive diagnostic and predictive assay for AD, MCI and PE.
Asunto(s)
Enfermedad de Alzheimer/sangre , Análisis Químico de la Sangre/métodos , Preeclampsia/sangre , Adulto , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides , Biomarcadores/sangre , Proteínas Sanguíneas/análisis , Disfunción Cognitiva/diagnóstico , Femenino , Pruebas Hematológicas/métodos , Humanos , Inmunohistoquímica , Fragmentos de Péptidos , Preeclampsia/diagnóstico , Embarazo , Agregado de Proteínas/fisiología , Curva ROC , Trofoblastos/efectos de los fármacos , alfa-Sinucleína , Proteínas tauRESUMEN
Sensor-augmented insulin pump therapy with a predictive low glucose suspend (SAP-PLGS) feature is a remarkably progressed modality for the glycemic management of patients with type 1 diabetes. This technology avoids nocturnal hypoglycemia and severe hypoglycemia. A Brazilian woman developed type 1 diabetes at age 11 and was treated with multiple daily insulin injections. At age 20, she was admitted to our internal medicine department for her first pregnancy. Her HbA1c was 7.9% in the 6 weeks of gestation. Although the combination of continuous subcutaneous insulin infusion and a sensor-augmented pump was introduced, she had a miscarriage in the next week. After 6 months, she became pregnant again. Despite an HbA1c of 7.2%, she had another miscarriage. Thereafter, she returned to multiple daily insulin injections and began using intermittently scanned continuous glycemic monitoring. At age 22, she had her third pregnancy. Her HbA1c was 7.3%. SAP-PLGS was then introduced, which reduced her frequent hypoglycemic events and blood glucose fluctuations. She gave birth to a 4137 g boy at 39 weeks without significant complications. Successful delivery can be obtained in women with type 1 diabetes following repeated miscarriages after introducing SAP-PLGS. We hypothesize that the modality might contributed to our patient's miscarriage avoidance by reducing her glycemic fluctuations.
RESUMEN
Objective: The purpose of this study was to investigate perinatal factors associated with a poor neurodevelopmental outcome in preterm infants. Methods: A retrospective study was conducted by searching our clinical database between January 2006 and December 2016. A total of 165 singleton children who were born between 23 and 33 weeks of gestation were included. We defined poor neurological development outcomes as follows: cerebral palsy; intellectual disability; developmental disorder including autism and attention-deficit/hyperactivity disorder; low score (<85 points) on Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III); or low score of Kyoto Scale of Psychological Development corrected at 3 years old. We diagnosed maternal renal dysfunction according to the Clinical Practice Guideline for chronic kidney disease 2018 and the Best Practice Guide 2015 for Care and Treatment of Hypertension in Pregnancy. Results: The rate of poor neurological development was 25/165 (15.2%): cerebral palsy (n = 1), intellectual disability (n = 1), developmental disorder (n = 2), low score of Bayley-III (n = 20), and low score of Kyoto Scale of Psychological Development (n = 1). Preeclampsia complicated with maternal renal dysfunction (P = 0.045) and delivery at <30 weeks of gestation (P = 0.007) were independent risk factors for poor neurological development. Conclusions: In addition to previous risk factors such as delivery at <30 weeks of gestation, preeclampsia complicated with renal dysfunction was also associated with poor neurodevelopmental outcomes corrected at 3 years old.
RESUMEN
AIMS/HYPOTHESIS: The imbalance between maternal insulin resistance and a relative lack of insulin secretion underlies the pathogenesis of gestational diabetes mellitus (GDM). Alterations in T cell subtypes and increased levels of circulating proinflammatory cytokines have been proposed as potential mechanisms underlying the pathophysiology of insulin resistance in GDM. Since oestrogen modulates T cell immunity, we hypothesised that oestrogen plays a homeostatic role in visceral adipose tissue by coordinating T cell immunity through oestrogen receptor α (ERα) in T cells to prevent GDM. METHODS: Female CD4-cre ERαfl/fl (KO) mice on a C57BL/6 background with ERα ablation specifically in T cells, and ERαfl/fl (ERα-floxed [FL]) mice were fed 60 kJ% high-fat diet (HFD) for 4 weeks. Female mice mated with male BALB/c mice to achieve allogenic pregnancy and were maintained on an HFD to generate the GDM model. Mice were divided into four experimental groups: non-pregnant FL, non-pregnant KO, pregnant FL (FL-GDM) and pregnant KO (KO-GDM). GTTs and ITTs were performed on day 12.5 or 13.5 and 16.5 after breeding, respectively. On day 18.5 after breeding, mice were killed and T cell subsets in the gonadal white adipose tissue (gWAT) and spleen were analysed using flow cytometry. Histological examination was also conducted and proinflammatory gene expression in gWAT and the liver was evaluated. RESULTS: KO mice that mated with BALB/c mice showed normal fertility rates and fetal weights as compared with FL mice. Body and tissue weights were similar between FL and KO mice. When compared with FL-GDM mice, KO-GDM mice showed decreased insulin secretion (serum insulin concentration 15 min after glucose loading: 137.3 ± 18.3 pmol/l and 40.1 ± 36.5 pmol/l, respectively; p < 0.05), impaired glucose tolerance (glucose AUC in GTT: 2308.3 ± 54.0 mmol/l × min and 2620.9 ± 122.1 mmol/l × min, respectively; p < 0.05) and increased numbers of T helper (Th)17 cells in gWAT (0.4 ± 0.0% vs 0.8 ± 0.1%; p < 0.05). However, the contents of Th1 and regulatory T cells (Tregs) in gWAT remained similar between FL-GDM and KO-GDM. Glucose-stimulated insulin secretion was similar between isolated islets derived from FL and KO mice, but was reduced by IL-17A treatment. Moreover, the levels of proinflammatory gene expression, including expression of Emr1 and Tnfa in gWAT, were significantly higher in KO-GDM mice than in FL-GDM mice (5.1-fold and 2.7-fold, respectively; p < 0.01 for both). Furthermore, KO-GDM mice showed increased expression of genes encoding hepatokines, Ahsg and Fgf21 (both were 2.4-fold higher vs FL-GDM mice; p < 0.05 and p = 0.09, respectively), with no changes in inflammatory gene expression (e.g., Tnfa and Ifng) in the liver compared with FL-GDM mice. CONCLUSIONS/INTERPRETATION: Deletion of ERα in T cells caused impaired maternal adaptation of insulin secretion, changes in hepatokine profiles, and enhanced chronic inflammation in gWAT alongside an abnormal increase in Th17 cells. These results suggest that the ERα-mediated oestrogen signalling effects in T cells regulate T cell immunity and contribute to glucose homeostasis in pregnancy.
Asunto(s)
Diabetes Gestacional , Receptor alfa de Estrógeno/metabolismo , Glucosa/metabolismo , Linfocitos T/inmunología , Animales , Diabetes Gestacional/genética , Diabetes Gestacional/inmunología , Diabetes Gestacional/metabolismo , Diabetes Gestacional/patología , Modelos Animales de Enfermedad , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/fisiología , Femenino , Prueba de Tolerancia a la Glucosa , Resistencia a la Insulina/fisiología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Embarazo , Linfocitos T/metabolismoRESUMEN
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.
Asunto(s)
Macroautofagia , Placenta/fisiopatología , Preeclampsia/fisiopatología , Animales , Femenino , Humanos , Lisosomas/metabolismo , Placenta/metabolismo , Preeclampsia/etiología , Preeclampsia/metabolismo , Embarazo , Agregación Patológica de ProteínasRESUMEN
Fetal antigen-specific tolerance is important for maintaining allogeneic pregnancies. Maternal conventional T cells recognize fetal antigens; however, regulatory T (Treg) cells suppress immune reactions against the fetus. Fetal antigen-specific Treg cells are induced in the decidua upon contact with antigen-presenting cells and extravillous trophoblasts (EVTs). Functional alteration of cytotoxic T cells (CTLs) in the decidua also contributes to maintaining the pregnancy. Reduced, dysfunctional, and imbalanced Treg cell distribution likely contributes to the pathogenesis of pregnancy complications, such as miscarriage and preeclampsia. Recent studies have revealed differences in Treg cell characteristics during preeclampsia and miscarriage. Treg cell reduction in the decidua is likely associated with miscarriage. Insufficient expansion of fetal antigen-specific Treg cells in the decidua probably plays a role in preeclampsia pathogenesis. In addition, the balance between Treg cell-mediated tolerance and functional alteration of CTLs is important. Further investigations of functional molecules in Treg cells will contribute to the development of immunotherapy for pregnancy complications.
Asunto(s)
Decidua/inmunología , Inmunoterapia/métodos , Complicaciones del Embarazo/inmunología , Embarazo/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Citotoxicidad Inmunológica , Femenino , Histocompatibilidad Materno-Fetal , Humanos , Tolerancia Inmunológica , Complicaciones del Embarazo/terapiaRESUMEN
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.