title: 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.
authors.affiliation: Division of Reproductive Health, Warwick Medical School, Clinical Sciences Research Laboratories, University Hospital, Coventry, United Kingdom.
authors.forename: Madhuri S
authors.initials: MS
authors.lastname: Salker
authors.forename: Jaya
authors.initials: J
authors.lastname: Nautiyal
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Steel
authors.forename: Zoe
authors.initials: Z
authors.lastname: Webster
authors.forename: Sandra
authors.initials: S
authors.lastname: Sućurović
authors.forename: Marilena
authors.initials: M
authors.lastname: Nicou
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Singh
authors.forename: Emma S
authors.initials: ES
authors.lastname: Lucas
authors.forename: Keisuke
authors.initials: K
authors.lastname: Murakami
authors.forename: Yi-Wah
authors.initials: YW
authors.lastname: Chan
authors.forename: Sean
authors.initials: S
authors.lastname: James
authors.forename: Yazan
authors.initials: Y
authors.lastname: Abdallah
authors.forename: Mark
authors.initials: M
authors.lastname: Christian
authors.forename: B Anne
authors.initials: BA
authors.lastname: Croy
authors.forename: Biserka
authors.initials: B
authors.lastname: Mulac-Jericevic
authors.forename: Siobhan
authors.initials: S
authors.lastname: Quenby
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Brosens
mesh_terms: D000026:Abortion, Habitual / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D019898:Autocrine Communication; D002454:Cell Differentiation; D003656:Decidua / Q000166:cytology / Q000473:pathology* / Q000502:physiology / Q000503:physiopathology; D010064:Embryo Implantation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: C079241:IL1RL1 protein, human; C506536:IL33 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D011956:Receptors, Cell Surface