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Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy loss
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Salker, Madhuri S., Nautiyal, Jaya, Steel, Jennifer H., Webster, Zoe, Šućurović, Sandra, Nicou, Marilena, Singh, Yogesh, Dr., Lucas, Emma S., Murakami, Keisuke, Chan, Yi-Wah, James, Sean G., Abdallah, Yazan, Christian, Mark, Croy, B. A. (B. Anne), Mulac-Jericevic, Biserka, Quenby, Siobhan and Brosens, Jan J. (2012) Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy loss. PLoS One, Vol.7 (No.12). e52252. doi:10.1371/journal.pone.0052252
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Official URL: http://dx.doi.org/10.1371/journal.pone.0052252
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.
| Item Type: | Journal Article | ||||
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| Subjects: | R Medicine > RG Gynecology and obstetrics | ||||
| Divisions: | Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Reproductive Health ( - until July 2016) Faculty of Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Decidua -- Physiology, Ovum implantation | ||||
| Journal or Publication Title: | PLoS One | ||||
| Publisher: | Public Library of Science | ||||
| ISSN: | 1932-6203 | ||||
| Official Date: | December 2012 | ||||
| Dates: |
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| Volume: | Vol.7 | ||||
| Number: | No.12 | ||||
| Page Range: | e52252 | ||||
| DOI: | 10.1371/journal.pone.0052252 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Open Access | ||||
| Funder: | University Hospitals Coventry and Warwickshire NHS Trust, Warwick Medical School, Genesis Research Trust |
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