Immune activation at the maternal-fetal interface is a main pathogenic factor of preeclampsia (PE). Neutrophils (PMNs) are activated in PE patients, but the mechanism and consequences of PMN activation need to be further explored. Here, we demonstrated that interleukin-32 (IL-32) expression was significantly upregulated in syncytiotrophoblasts (STBs) and that IL-32β was the major isoform with increased expression in the placenta of severe PE (sPE) patients. Furthermore, the level of IL-32 expression in the placenta was correlated with its level in the serum of sPE patients, indicating that IL-32 in the serum is derived mainly from the placenta. Then, in vitro experiments showed that IL-32β could highly activate PMNs and that these IL-32β-activated PMNs were better able to adhere to endothelial cells (HUVECs) and enhance the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) in HUVECs, which could be reversed by preincubation with the NADPH oxidase inhibitor VAS 2870. In addition, we showed that IL-32β mainly activated PMNs by binding to proteinase 3. Finally, IL-32β administration induced a PE-like phenotype in a pregnant mouse model. This study provides evidence of the involvement of IL-32β in the pathogenesis of PE.
Intrauterine adhesions (IUA), the leading cause of uterine infertility, are characterized by endometrial fibrosis. The management of IUA is challenging because the pathogenesis of the disease largely unknown. In this study, we demonstrate that the mRNA and protein levels of HMGA2 were increased by nearly 3-fold (P < 0.0001) and 5-fold (P=0.0095) in the endometrial epithelial cells (EECs) of IUA patients (n = 18) compared to controls. In vivo and in vitro models of endometrial fibrosis also confirmed the overexpression of HMGA2 in EECs. In vitro cell experiments indicated that overexpression of HMGA2 promoted the epithelial-mesenchymal transition (EMT) while knockdown of HMGA2 reversed TGF-β-induced EMT. A dual luciferase assay confirmed let-7d microRNA downregulated HMGA2 and repressed the pro-EMT effect of HMGA2 in vitro and in vivo. Therefore, our data reveal that HMGA2 promotes IUA formation and suggest that let-7d can depress HMGA2 and may be a clinical targeting strategy in IUA.
BACKGROUND: Preeclampsia is a complicated syndrome with marked heterogeneity. The biomarker-based classification for this syndrome is more constructive to the targeted prevention and treatment of preeclampsia. It has been reported that preeclamptic patients had elevated miR-155 in placentas or circulation. Here, we investigated the characteristics of patients with high placental miR-155 (pl-miR-155). METHODS: Based on the 95th percentile (P95) of pl-miR-155 in controls, preeclamptic patients were divided into high miR-155 group (≥P95) and normal miR-155 group (<P95). The changes of placental pathology, clinical manifestations, and placental transcriptome of preeclamptic patients were clustered by t-distributed stochastic neighbor embedding and hierarchical clustering analysis. The placental restricted miR-155 overexpression mouse model was constructed, and the phenotype, placental pathology, and transcriptome were evaluated. Furthermore, the therapeutic potential of antagonist of miR-155 was explored by administrating with antagomir-155. RESULTS: About one-third of preeclamptic patients had high pl-miR-155 expression, which was positively correlated with circulating miR-155 levels. These patients could be clustered as 1 group, according to clinical manifestation, placental pathology, or transcriptomes by t-distributed stochastic neighbor embedding and hierarchical clustering analysis. Further, the pregnant mice with placental restricted miR-155 overexpression could simulate the changes of clinical signs, pathology, and transcriptome of placentas in patients with high pl-miR-155. AntagomiR-155 treatment relieved the preeclampsia-like phenotype and improved the placental vascular development in mice. CONCLUSIONS: There is at least 1 type of preeclampsia with upregulated miR-155 presenting more severe clinical manifestations. MiR-155 may be a potential therapeutic target in patients with high pl-miR-155.
Preeclampsia is a heterogeneous disorder which affect maternal and fetal outcomes. The current classifications of preeclampsia such as "early- " and "late-" types, and "mild" and "severe" forms, are too imprecise to delineate the pathophysiology of preeclampsia. Here we reported that roughly one third of preeclampsia patients had high expression of maternal serum miR-155 in the case-control study and longitudinal study. The maternal serum miR-155 increased as early as 11-13+6 weeks of gestation. The patients with high serum miR-155 had severer clinical symptoms such as higher blood pressure and urine protein, and more adverse maternal and fetal outcomes. Moreover, these patients could be clustered as one group according to clinical manifestation by t-distributed stochastic neighbor embedding analysis. Therefore, these data suggest that preeclamptic patients with high maternal serum miR-155 could be viewed as a subtype of preeclampsia.
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