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The role of smooth muscle cell-derived IL-18 in uterine immune milieu and fetoplacental growth

ABSTRACT: There is a close relationship between pregnancy and immune responses. For example, an anti-inflammatory state is essential for maintaining pregnancy by promoting maternal tolerance toward the semi-allogeneic fetus, whereas pro-inflammatory conditions are crucial for processes such as maternal tissue remodeling during embryo implantation and the induction of labor. Increasing evidence suggests that various cell types within the uteroplacental immune environment contribute to these immune responses, and immunological approaches have been employed to investigate the pathophysiology and potential treatments of pregnancy-related complications. Interleukin-18 (IL-18) is a unique cytokine with both pro-inflammatory and anti-inflammatory properties; however, its roles during pregnancy remain largely unclear. We have found that smooth muscle cells (SMCs) in the uterine myometrium are an important source of IL-18, and that the homeostatic production of IL-18 promotes fetal development by supporting maternal uterine remodeling and placental growth. To further investigate the effects of IL-18 on the uterine immune milieu, we established SMC-specific Il18 conditional knockout (cKO) mice and performed RNA sequencing of uterine immune cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE293908 | GEO | 2025/04/18

REPOSITORIES: GEO

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Project description:Prior to pregnancy, hormonal changes lead to cellular adaptations in the endometrium allowing for embryo implantation. Critical for successful pregnancy establishment, innate immune cells constitute a significant proportion of uterine cells prior to arrival of the embryo and throughout the first trimester in humans and animal models. Abnormal uterine immune cell function during implantation is believed to play a role in multiple adverse pregnancy outcomes. Current work in humans has focused on uterine immune cells present after pregnancy establishment, and limited in vitro models exist to explore unique functions of these cells. With single-cell RNA-sequencing (scRNAseq), we comprehensively compared the human uterine immune landscape of the endometrium during the window of implantation and the decidua during the first trimester of pregnancy. We uncovered global and cell-type-specific gene signatures for each timepoint. Immune cells in the endometrium prior to implantation expressed genes associated with immune metabolism, division, and activation. In contrast, we observed widespread interferon signaling during the first trimester of pregnancy. We also provide evidence of specific inflammatory pathways enriched in pre- and post-implantation macrophages and natural killer (NK) cells in the uterine lining. Using our novel implantation-on-a-chip (IOC) to model human implantation ex vivo, we demonstrate for the first time that uterine macrophages strongly promote invasion of extravillous trophoblasts (EVTs), a process essential for pregnancy establishment. Pre- and post-implantation uterine macrophages promoted EVT invasion to a similar degree as pre- and post-implantation NK cells on the IOC. This work provides a foundation for further investigation of the individual roles of uterine immune cell subtypes present prior to embryo implantation and during early pregnancy, which will be critical for our understanding of pregnancy complications associated with abnormal trophoblast invasion and placentation.

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The role of smooth muscle cell-derived IL-18 in uterine immune milieu and fetoplacental growth

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