Disordered IL-33/ST2 Activation in Decidualizing Stromal Cells Prolongs Uterine Receptivity in Women with Recurrent Pregnancy Loss

被引:169
作者
Salker, Madhuri S. [1 ,2 ]
Nautiyal, Jaya [2 ]
Steel, Jennifer H. [2 ]
Webster, Zoe [3 ]
Sucurovic, Sandra [1 ,4 ]
Nicou, Marilena [2 ]
Singh, Yogesh [5 ]
Lucas, Emma S. [1 ]
Murakami, Keisuke [1 ]
Chan, Yi-Wah [1 ]
James, Sean [1 ]
Abdallah, Yazan [1 ]
Christian, Mark [2 ]
Croy, B. Anne [6 ]
Mulac-Jericevic, Biserka [4 ]
Quenby, Siobhan [1 ]
Brosens, Jan J. [1 ]
机构
[1] Univ Hosp, Clin Sci Res Labs, Warwick Med Sch, Div Reprod Hlth, Coventry, W Midlands, England
[2] Univ London Imperial Coll Sci Technol & Med, Inst Reprod & Dev Biol, London, England
[3] Univ London Imperial Coll Sci Technol & Med, Embryon Stem Cell Facil, MRC, Ctr Clin Sci, London, England
[4] Univ Rijeka, Dept Physiol & Immunol, Sch Med, Rijeka, Croatia
[5] Univ London Royal Vet Coll, Dept Infect & Immun, London, England
[6] Queens Univ, Dept Biomed & Mol Sci, Kingston, ON, Canada
关键词
SOLUBLE ST2; ENDOMETRIAL RECEPTIVITY; INDIAN HEDGEHOG; CROSS-TALK; PROGESTERONE; RECEPTOR; IMPLANTATION; INTERLEUKIN-33; EMBRYO; GENE;
D O I
10.1371/journal.pone.0052252
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:18
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