Dynamic Expression of Interleukin-33 and ST2 in the Mouse Reproductive Tract Is Influenced by Superovulation

Abstract

Interleukin-33 (IL-33) is an IL-1 family cytokine with pleiotropic effects on diverse cell types. Dysregulated IL-33 signaling has been implicated in pregnancy-related disorders, including preeclampsia and recurrent pregnancy loss, and in ovarian function in women undergoing controlled ovarian stimulation for in vitro fertilization. To date, expression of IL-33 and its receptor subunit, ST2, in the female reproductive tract remains poorly characterized. We identify IL-33-expressing oocytes surrounded by ST2-expressing granulosa cells at all stages of follicular development, in addition to IL-33+ and ST2+ non-endothelial cells in the ovarian stroma and theca layer in ovaries from adult mice. These expression patterns are similar in estrus- and diestrus-stage adults and in pubescent mice, suggesting a role for IL-33 signaling in ovarian function throughout development and in the estrous cycle. In the uterus, we find expression of IL-33 and ST2 in glandular and luminal epithelia during estrus and at the initiation of pregnancy. Uterine IL-33 expression was modulated by the estrous cycle and was reduced in pubescent females. Last, superovulation increases transcripts for IL-33 and the soluble form of ST2 (sST2) in ovaries, and for IL-33 in uteri. Collectively, our findings lay the foundation for studies identifying cell type-specific requirements for IL-33/ST2 signaling in the establishment and maintenance of mouse pregnancy.

Maternal IL-33 critically regulates tissue remodeling and type 2 immune responses in the uterus during early pregnancy in mice

“…However, whether and how IL-33 supports events that precede implantation are less clear. While we find that total implantation site numbers at E7.5 are reduced in IL-33 KO dams, the modest nature of this reduction suggests that IL-33 may play relatively minor roles in the reproductive processes that are required to initiate implantation in mice—such as oogenesis and oocyte release during estrus, oocyte fertilization, and blastocyst attachment—notwithstanding our prior finding that IL-33 is expressed in the ovaries and uteri of virgin mice and through E2.5 in pregnancy ( 50 ).…”

“…The relative, stage-specific requirements for IL-33 in early pregnancy progression may reflect differences in the uterine cell types that express IL-33 in the pre- versus post-implantation stages of early pregnancy. For example, we have previously shown that glandular and luminal epithelial cells are the main IL-33 + cells in the endometrium at E2.5 ( 50 ), whereas we now show that stromal cells and endothelial cells are the main IL-33 + cell types in the decidua during the post-implantation stage of early pregnancy, although IL-33 expression by decidual endothelial cells during this time frame is transient and peaks at E7.5. Our findings are consistent with a recent scRNA-seq study on mouse implantation sites at E5.5, which identified Il33 transcripts in Hoxa11 -positive decidual stromal cells arising during the “second wave” of decidualization that follows blastocyst implantation ( 51 ).…”

“…compound (Sakura), and cryosectioned at 7 µm. Immunostaining was performed, as described ( 50 ), using antibodies listed in SI Appendix , Table S1 . Two or three ISs per dam were analyzed, using at least three sections per IS.…”

Differences in maternal soluble ST2 levels in the third trimester of normal pregnancy versus preeclampsia

“…Regardless of the role ethnicity plays, since sST2 levels were not significantly influenced by age and BMI, our differences may have been caused by the range of gestational ages during blood collection. Our study had a slightly wider gestational age range compared to the previous study (30–38 and 30–34 weeks of gestation, respectively), which could contribute to these differences [10] , [15] , [16] , [17] . Concentrations of sST2 were relatively constant until 30 weeks of gestation, after which they increased steadily until the time of delivery due to changes in cytokine concentrations and in the volume of maternal circulation, both of which increased endothelial cell production of sST2 [11] .…”

Effects of neonatal exposure to methoxychlor on corpus luteum in gilts: A transcriptomic analysis

“…We also found upregulation of several immune‐related genes, such as interleukin 33 ( IL33 ), interleukin receptors ( IL4R , IL21R , IL10RA ), interleukin 1 receptor like 1 ( IL2RL1 ), monocytes‐derived plasminogen activator inhibitor 2 ( SERPINB2 ), eosinophil‐attracting chemokine ( CCL11 ), C‐C motif chemokine receptor 1 ( CCR1 ), syndecan binding protein 2 ( SDCBP2 ), which is a chemokine coreceptor, and the proinflammatory cytokine lipocaline 2 ( LCN2 ). IL33 expression is upregulated following proinflammatory stimulation (Begum et al, 2020), IL4 is produced by activated T‐cells and has a role in regulating porcine CL acting via ILR4 (Sakumoto et al, 2006), while IL21 inhibits angiogenesis acting via ILR21 in endothelial cells (Castermans et al, 2008). Moreover, eosinophils accumulate within the CL before regression, and were shown to be the most prominent blood cell type in the porcine regressing CL (Standaert et al, 1991).…”