Dataset Information

Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy loss.

ABSTRACT: Decidualization renders the endometrium transiently receptive to an implanting blastocyst although the underlying mechanisms remain incompletely understood. Here we show that human endometrial stromal cells (HESCs) rapidly release IL-33, a key regulator of innate immune responses, upon decidualization. In parallel, differentiating HESCs upregulate the IL-33 transmembrane receptor ST2L and other pro-inflammatory mediators before mounting a profound anti-inflammatory response that includes downregulation of ST2L and increased expression of the soluble decoy receptor sST2. We demonstrate that HESCs secrete factors permissive of embryo implantation in mice only during the pro-inflammatory phase of the decidual process. IL-33 knockdown in undifferentiated HESCs was sufficient to abrogate this pro-inflammatory decidual response. Further, sequential activation of the IL-33/ST2L/sST2 axis was disordered in decidualizing HESCs from women with recurrent pregnancy loss. Signals from these cultures prolonged the implantation window but also caused subsequent pregnancy failure in mice. Thus, Il-33/ST2 activation in HESCS drives an autoinflammatory response that controls the temporal expression of receptivity genes. Failure to constrain this response predisposes to miscarriage by allowing out-of-phase implantation in an unsupportive uterine environment.

SUBMITTER: Salker MS

PROVIDER: S-EPMC3531406 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy loss.

Salker Madhuri S MS Nautiyal Jaya J Steel Jennifer H JH Webster Zoe Z Sućurović Sandra S Nicou Marilena M Singh Yogesh Y Lucas Emma S ES Murakami Keisuke K Chan Yi-Wah YW James Sean S Abdallah Yazan Y Christian Mark M Croy B Anne BA Mulac-Jericevic Biserka B Quenby Siobhan S Brosens Jan J JJ

PloS one 20121227 12

Decidualization renders the endometrium transiently receptive to an implanting blastocyst although the underlying mechanisms remain incompletely understood. Here we show that human endometrial stromal cells (HESCs) rapidly release IL-33, a key regulator of innate immune responses, upon decidualization. In parallel, differentiating HESCs upregulate the IL-33 transmembrane receptor ST2L and other pro-inflammatory mediators before mounting a profound anti-inflammatory response that includes downreg ...[more]

PMID: 23300625

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Project description:BackgroundThe optimization of endometrial receptivity (ER) through individualized therapies has been shown to enhance the likelihood of successful gestation. However, current practice lacks comprehensive methods for evaluating the ER of patients with recurrent pregnancy loss (RPL). Radiomics, an emerging AI-based technique that enables the extraction of mineable information from medical images, holds potential to offer a more objective and quantitative approach to ER assessment. This innovative tool may facilitate a deeper understanding of the endometrial environment and enable clinicians to optimize ER evaluation in RPL patients.ObjectiveThis study aimed to identify ultrasound radiomics features associated with ER, with the purpose of predicting successful ongoing pregnancies in RPL patients, and to assess the predictive accuracy of these features against regular ER parameters.MethodsThis retrospective, controlled study involved 262 patients with unexplained RPL and 273 controls with a history of uncomplicated full-term pregnancies. Radiomics features were extracted from ultrasound endometrial segmentation images to derive a radiomics score (rad-score) for each participant. Associations between rad-scores, baseline clinical variables, and sonographic data were evaluated using univariate and multivariate logistic regression analyses to identify potential indicators of RPL. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive accuracy of the rad-score and other identified indicators in discriminating RPL cases. Furthermore, the relationships between age and these identified indicators were assessed via Pearson correlation analysis.ResultsFrom the 1312 extracted radiomics features, five non-zero coefficient radiomics signatures were identified as significantly associated with RPL, forming the basis of the rad-score. Following multivariate logistic regression analysis, age, spiral artery pulsatility index (SA-PI), vascularisation index (VI), and rad-score emerged as independent correlates of RPL (all P<0.05). ROC curve analyses revealed the superior discriminative capability of the rad-score (AUC=0.882) over age (AUC=0.778), SA-PI (AUC=0.771), and VI (AUC=0.595). There were notable correlations between age and rad-score (r=0.275), VI (r=-0.224), and SA-PI (r=0.211), indicating age-related variations in RPL predictors.ConclusionThis study revealed a significant association between unexplained RPL and elevated endometrial rad-scores during the WOI. Furthermore, it demonstrated the potential of rad-scores as a promising predictive tool for successful ongoing pregnancies in RPL patients.

Project description:Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis.

Dataset Information

Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy loss.

Publications

Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy loss.

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