RESUMO
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has devastating effects on the population worldwide. Given this scenario, the extent of the impact of the disease on more vulnerable individuals, such as pregnant women, is of great concern. Although pregnancy may be a risk factor in respiratory virus infections, there are no considerable differences regarding COVID-19 severity observed between pregnant and nonpregnant women. In these circumstances, an emergent concern is the possibility of neurodevelopmental and neuropsychiatric harm for the offspring of infected mothers. Currently, there is no stronger evidence indicating vertical transmission of SARS-CoV-2; however, the exacerbated inflammatory response observed in the disease could lead to several impairments in the offspring's brain. Furthermore, in the face of historical knowledge on possible long-term consequences for the progeny's brain after infection by viruses, we must consider that this might be another deleterious facet of COVID-19. In light of neuroimmune interactions at the maternal-fetal interface, we review here the possible harmful outcomes to the offspring brains of mothers infected by SARS-CoV-2.
Assuntos
COVID-19/imunologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Neuroimunomodulação/imunologia , Complicações Infecciosas na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , COVID-19/metabolismo , COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/imunologia , Decídua/imunologia , Feminino , Humanos , Tolerância Imunológica/imunologia , Transmissão Vertical de Doenças Infecciosas , Neuroimunomodulação/fisiologia , Placenta/imunologia , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/fisiopatologia , SARS-CoV-2 , Cordão Umbilical/imunologiaRESUMO
During pregnancy, prolactin (PRL) is a neuro-immuno-cytokine that contributes actively to the crosstalk between the immune and endocrine systems and, thus, to the creation of an immune-privileged milieu. This work aims to analyze the capacity of PRL to modulate the synthesis and secretion of pro-inflammatory markers associated with labor. Studies were conducted using human fetal membranes at term mounted in a model of two independent chambers. The choriodecidual region was stimulated with 500-ng/mL lipopolysaccharide (LPS), and the amnion and choriodecidual region were co-simulated with different concentrations of PRL that can arise during pregnancy: 250, 500, 1000, and 4000ng/mL. Following these co-treatments, the tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-10 levels were measured in both compartments. As expected, treatment with LPS induced all cytokines to increase. Co-stimulation with the highest tested concentration of PRL induced significant decreases in TNF-α in the choriodecidual region and IL-1ß in both regions of the fetal membranes. PRL did not modified the IL-6 and IL-10 secretion profile. These findings, coupled with clinical evidence, suggest that the high level of PRL in the amniotic cavity is involved the mechanism by which the fetal-placental unit regulates the equilibrium between pro- and anti-inflammatory modulators.
Assuntos
Âmnio/imunologia , Anti-Inflamatórios/metabolismo , Decídua/imunologia , Prolactina/metabolismo , Células Cultivadas , Feminino , Humanos , Imunomodulação , Mediadores da Inflamação/metabolismo , Interleucina-10/metabolismo , Lipopolissacarídeos/imunologia , Neuroimunomodulação , Técnicas de Cultura de Órgãos , Circulação Placentária , GravidezRESUMO
Pregnancy is a complex process where several physiological pathways interact. The down-regulated inflammatory response and the abundance of anti-inflammatory molecules during gestation may explain the acceptance of the fetus and the lack of immune response against it, even though it is a foreign tissue for the mother. NF-κB is a key regulator of the transcription of inflammatory genes, such as IL-8, IL-1ß, TNF-α, or IL-6. Increased NF-κB activity that leads to the production of proinflammatory cytokines may induce obstetric disorders, such as preterm birth or abortion. Low activity of this transcription factor is associated with the beneficial anti-inflammatory environment during fetus development until delivery. Galectin-1 (Gal-1) is a lectin-type glycan-binding protein that is able to down-regulate inflammation. It has been shown that Gal-1 is abundantly expressed at the feto-maternal interface in humans, where it promotes maternal immune tolerance to the fetal semi-allograft. Gal-1 tolerance-promoting mechanisms have been established for adaptive immune cells, such as T cells and dendritic cells. However, the role of this lectin has not been established in non-immune cells at the feto-maternal interface. Here, we determined that Gal-1 is able to block the stimulating effect of LPS on IL-6 in human decidua cells. Our results show that Gal-1 acts by inhibiting the stimulation of the LPS-induced IκBζ expression, an NF-κB regulator involved in IL-6 gene transcription.
Assuntos
Decídua/imunologia , Galectina 1/imunologia , Proteínas I-kappa B/imunologia , Interleucina-6/imunologia , Lipopolissacarídeos/toxicidade , Placenta/imunologia , Proteínas Proto-Oncogênicas/imunologia , Adulto , Células Cultivadas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Gravidez , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/imunologiaRESUMO
INTRODUCTION: Escherichia coli is recognized as an etiological bacteria associated with chorioamnionitis and the preterm premature rupture of fetal membranes. This pathological condition induces pro-inflammatory cytokines and degradative metalloproteinases, which are considered biological markers secreted in an acute stage of infection. Heat-shock proteins (HSPs) are an important component of the innate immunity response and are found in different pathological conditions. They have not been previously measured in human fetal membranes in response to infectious conditions. We hypothesized that the choriodecidual tissue and amniotic epithelium secreted temporal and differential Hsp-60, Hsp-70, and interleukin (IL)-1ß mediated by E. coli infection. METHODS: Fetal membranes were mounted in a two-compartment culture system and infected with two passes of live E. coli at different doses (10², 104, 105, and 106 colony-forming units (CFU)/mL) and intervals of incubation (3, 6, and 24 h). The culture medium was collected, and Hsp-60, Hsp-70, and IL-1ß were assessed using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: After 3 and 6 h of infection, E. coli induced an increase in Hsp-70 secretion in the choriodecidual tissue. However, after 24 h of incubation, Hsp-70 was downregulated and we observed an increase in IL-1ß secretion. By contrast, E. coli induced a lower Hsp-60 secretion in the amnion compared to Hsp-70. DISCUSSION: Human fetal membranes responded actively to E. coli infection, with an increase in Hsp-70 during the first hours of infection. After 24 h, there was an increase in the liberation of IL-1ß.
Assuntos
Escherichia coli/imunologia , Membranas Extraembrionárias/metabolismo , Membranas Extraembrionárias/microbiologia , Proteínas de Choque Térmico HSP110/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Interleucina-1beta/metabolismo , Regulação para Cima , Âmnio/imunologia , Âmnio/metabolismo , Âmnio/microbiologia , Chaperonina 60/metabolismo , Corioamnionite/imunologia , Corioamnionite/metabolismo , Corioamnionite/microbiologia , Córion/imunologia , Córion/metabolismo , Córion/microbiologia , Decídua/imunologia , Decídua/metabolismo , Decídua/microbiologia , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Membranas Extraembrionárias/imunologia , Feminino , Humanos , Imunidade Inata , Cinética , Proteínas Mitocondriais/metabolismo , Gravidez , Técnicas de Cultura de TecidosRESUMO
OBJECTIVE: To evaluate whether progesterone (P4) is able to modulate the secretion of tumour necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-8, IL-10 and matrix metalloproteinase-9 (MMP-9) after choriodecidual stimulation with lipopolysaccharide (LPS). DESIGN: Chorioamnionitis-elicited preterm delivery is associated with an uncontrolled secretion of proinflammatory cytokines that may induce MMPs, which modify the fine immunological and structural equilibrium at the fetal-maternal interface. SETTING: Instituto Nacional de Perinatología 'Isidro Espinosa de los Reyes', Mexico City. SAMPLE: Twelve human fetal membranes at term from healthy patients were placed in a two-chamber culture system. METHODS: Choriodecidual and amniotic regions were preincubated with 1.0, 0.1, or 0.01 µmol/l P4 for 24 hours; after which the choriodecidual region was costimulated with 1000 ng/ml of LPS for 24 hours. MAIN OUTCOME MEASURES: Descriptive statistics were obtained for each variable. Data distribution was tested for normality using Kolmogorov-Smirnoff and Shapiro-Wilk tests. When distribution was normal, Student's t test was used to analyse for differences among groups. Mann-Whitney's U test was used when data were not normally distributed. RESULTS: Pretreatment with 1.0 µmol/l P4 significantly blunted the secretion of TNF-α, IL-1ß, IL-6, IL-8 and IL-10. MMP-9 was inhibited with 0.1 µmol/l P4. Mifepristone (RU486) blocked the immunosuppressive effect of P4, suggesting a P4 effect mediated by its receptor. CONCLUSION: These results offer evidence to support the concept that P4 can protect the fetal-placental unit through a compensatory mechanism that partially limits the secretion of proinflammatory and prodegradative modulators.
Assuntos
Citocinas , Decídua/efeitos dos fármacos , Membranas Extraembrionárias/efeitos dos fármacos , Progesterona/farmacologia , Progestinas/farmacologia , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Decídua/imunologia , Ensaio de Imunoadsorção Enzimática , Membranas Extraembrionárias/imunologia , Feminino , Humanos , Interleucina-10/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-6/metabolismo , Interleucina-8/efeitos dos fármacos , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Progesterona/imunologia , Progestinas/imunologia , Estatísticas não Paramétricas , Fator de Necrose Tumoral alfa/efeitos dos fármacosRESUMO
PROBLEM: Human parturition is associated with an intrauterine pro-inflammatory environment in the choriodecidua. Evidence that some mediators of this signaling cascade also elicit responses leading to labor prompted us to characterize the cellular sources of these mediators in the human choriodecidua. METHOD OF STUDY: Leukocyte-enriched preparations from human choriodecidua (ChL) and intervillous placental blood leukocytes (PL) were maintained in culture. Secretions of inflammatory cytokines, chemokines, and MMP-9 were documented. Leukocyte phenotype of ChL and PL was determined by flow cytometry using specific fluorochrome-conjugated antibodies. RESULTS AND CONCLUSIONS: ChL showed a distinct pro-inflammatory secretion pattern of cytokines and chemokines when compared with PL, including higher amounts of TNF-α and IL-6, and decreased secretions of IL-4 and IL-1ra. ChL also secreted more MIP-1α and MCP-1 and MMP-9 than PL. No significant differences were found in leukocytes subsets between compartments. Based on our findings, we propose that ChL isolated from fetal membranes at term are functionally different from PL and may collaborate to modulate the microenvironment linked to induction and progression of human labor.
Assuntos
Córion/imunologia , Decídua/imunologia , Leucócitos Mononucleares/imunologia , Subpopulações de Linfócitos/imunologia , Placenta/imunologia , Células Cultivadas , Microambiente Celular , Citocinas/metabolismo , Feminino , Humanos , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Gravidez , Nascimento a Termo/imunologiaRESUMO
PROBLEM: Spontaneous labor at term involves leukocyte recruitment and infiltration into the choriodecidua; yet, characterization of these leukocytes and their immunological mediators is incomplete. The purpose of this study was to characterize the immunophenotype of choriodecidual leukocytes as well as the expression of inflammatory mediators in human spontaneous parturition at term. METHOD OF STUDY: Choriodecidual leukocytes were analyzed by FACS, immunohistochemistry, and RT-PCR in three different groups: (i) preterm gestation delivered for medical indications without labor; (ii) term pregnancy without labor; and (iii) term pregnancy after spontaneous labor. RESULTS: Two T-cell subsets of memory-like T cells (CD3(+) CD4(+) CD45RO(+) and CD3(+) CD4(-) CD8(-) CD45RO(+) cells) were identified in the choriodecidua of women who had spontaneous labor. Evidence for an extensive immune signaling network composed of chemokines (CXCL8 and CXCL10), chemokine receptors (CXCR1-3), cytokines (IL-1ß and TNF-α), cell adhesion molecules, and MMP-9 was identified in these cells during spontaneous labor at term. CONCLUSIONS: The influx of memory-like T cells in the choriodecidua and the evidence that they are active by producing chemokines and cytokines, and expressing chemokine receptors, cell adhesion molecules, and a matrix-degrading enzyme provides support for the participation of the adaptive immune system in the mechanisms of spontaneous parturition at term.
Assuntos
Imunidade Adaptativa , Decídua/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Antígenos CD/metabolismo , Separação Celular , Células Cultivadas , Quimiocina CXCL10/metabolismo , Citocinas/metabolismo , Membranas Extraembrionárias/imunologia , Feminino , Citometria de Fluxo , Humanos , Memória Imunológica , Mediadores da Inflamação/metabolismo , Interleucina-8/metabolismo , Parto/imunologia , Gravidez , Receptores de Citocinas/metabolismo , Transdução de SinaisRESUMO
Three Nod-like receptors (NLR family, pyrin domain containing 1/NLRP1, NLR family, pyrin domain containing 3/NLRP3, NLR family, CARD domain containing 4/NLRC4) and the adaptor molecule PYD and CARD domain containing protein/PYCARD are involved in the assembling of multiprotein complexes known as inflammasomes, leading to caspase 1 activation and consequent interleukin (IL)-1ß secretion. Considering that inflammasomes are involved in sensing pathogens and in triggering inflammatory and immune response, we hypothesized that they could also act in the placenta as an efficient innate mechanism during pregnancy infections. For this reason the activation of inflammasome was tested in 3 human placental cell populations in the presence of a common gram-negative compound (lipopolysaccharide [LPS]). The transcription of NLRP1, NLRP3, NLRC4, PYCARD, CASP1, and IL1B genes and the secretion of IL-1ß were evaluated in human first trimester cytotrophoblasts (CTBs), decidual stromal cells (DSCs), and endothelial cells (DECs) stimulated with LPS. In CTBs and DSCs, LPS induced an augmented expression of CASP1 and IL1B and the specific upregulation of NLRP3 within the 3 NLRs tested. Moreover, LPS induced secretion of IL-1ß from CTBs and DSCs. These results suggest the involvement of NLRP3 inflammasome in the placental innate response. The LPS did not affect inflammasome gene transcription and IL-1ß production in DECs. Bacterial LPS enhances NLRP3 inflammasome components in trophoblast and DSCs, suggesting that this innate immune complex could play a key role in placental immune defense.
Assuntos
Decídua/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Endotoxinas/farmacologia , Inflamassomos/efeitos dos fármacos , Interleucina-1beta/metabolismo , Células Estromais/efeitos dos fármacos , Trofoblastos/efeitos dos fármacos , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Células Cultivadas , Decídua/imunologia , Células Endoteliais/imunologia , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamassomos/genética , Inflamassomos/imunologia , Interleucina-1beta/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR , Gravidez , Primeiro Trimestre da Gravidez , RNA Mensageiro/metabolismo , Células Estromais/imunologia , Fatores de Tempo , Transcrição Gênica , Trofoblastos/imunologiaRESUMO
BACKGROUND: During intrauterine infection, amniochorionic membranes represent a mechanical and immunological barrier against dissemination of infection. Human beta defensins (HBD)-1, HBD-2, and HBD-3 are key elements of innate immunity that represent the first line of defense against different pathogen microorganisms associated with preterm labor. The aim of this work was to characterize the individual contribution of the amnion (AMN) and choriodecidua (CHD) regions to the secretion of HBD-1, HBD-2 and HBD-3, after stimulation with Candida albicans. METHODS: Full-thickness human amniochorionic membranes were obtained after delivery by elective cesarean section from women at 37-40 wk of gestation with no evidence of active labor. The membranes were cultured in a two-compartment experimental model in which the upper compartment is delimited by the amnion and the lower chamber by the choriodecidual membrane. One million of Candida albicans were added to either the AMN or the CHD face or to both and compartmentalized secretion profiles of HBD-1, HBD-2, and HBD-3 were quantified by ELISA. Tissue immunolocalization was performed to detect the presence of HBD-1, -2, -3 in tissue sections stimulated with Candida albicans. RESULTS: HBD-1 secretion level by the CHD compartment increased 2.6 times (27.30 [20.9-38.25] pg/micrograms protein) when the stimulus with Candida albicans was applied only on this side of the membrane and 2.4 times (26.55 [19.4-42.5] pg/micrograms protein) when applied to both compartments simultaneously. HBD-1 in the amniotic compartment remained without significant changes. HBD-2 secretion level increased significantly in the CHD when the stimulus was applied only to this region (2.49 [1.49-2.95] pg/micrograms protein) and simultaneously to both compartments (2.14 [1.67- 2.91] pg/micrograms protein). When the stimulus was done in the amniotic compartment HBD-2 remained without significant changes in both compartments. HBD-3 remained without significant changes in both compartments regardless of the stimulation modality. Localization of immune-reactive forms of HBD-1, HBD-2, and HBD-3 was carried out by immunohistochemistry confirming the cellular origin of these peptides. CONCLUSION: Selective stimulation of amniochorionic membranes with Candida albicans resulted in tissue-specific secretion of HBD-1 and HBD-2, mainly in the CHD, which is the first region to become infected during an ascending infection.
Assuntos
Âmnio/imunologia , Candida albicans/imunologia , Córion/imunologia , beta-Defensinas/metabolismo , Âmnio/metabolismo , Candidíase/imunologia , Córion/metabolismo , Decídua/imunologia , Decídua/metabolismo , Feminino , Idade Gestacional , Humanos , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Técnicas de Cultura de TecidosRESUMO
PROBLEM: Preterm labor associated with infection is a major clinical condition; in this work, we analyze the response of human chorioamniotic membranes stimulated with Gardnerella vaginalis. METHOD OF STUDY: Using a two-compartment experimental model, 1 × 10(6) CFU/mL of G. vaginalis were added to either the amnion or choriodecidua face or to both. Concentrations of IL-1ß, TNF-α, and IL-6, as well as human beta defensins (HBD) 1-3 were quantified by ELISA. RESULTS: In comparison with control conditions and regardless of the stimulation modality, IL-1ß and IL-6 increased 4-fold and 28-fold, respectively, in the choriodecidual compartment. HBD-1 increased 2-fold mainly in the amniotic compartment when the stimulus was applied directly to this region. HBD-2 and HBD-3 increased an average of 2- and 8-fold, respectively, in the choriodecidual region. CONCLUSIONS: Stimulation with G. vaginalis induced a tissue-specific secretion profile of 1L-1ß, IL-6, and HBD 1-3 in the chorioamniotic membranes.