IL-18 produced by pregnant uterus promotes essential inflammatory responses and fetoplacental growth

Abstract

Placental insufficiency affects fetomaternal health throughout life. Although the interaction between the maternal uterine immune milieu and fetal-derived cells plays a crucial role in placental formation, several aspects remain unclear. Therefore, we conducted this study to investigate the effects of interleukin (IL)- 18, a unique cytokine with both proinflammatory and anti-inflammatory properties, on the uterine immune milieu and placental development. Our results identified pregnant uterine smooth muscle cells as an important source of IL-18, which supports homeostatic type 1 immune responses. IL-18 facilitates appropriate placental development through uterine vascular remodeling and placental angiogenesis. Smooth muscle cell-specific Il18-knockout dam mice exhibited impaired fetoplacental growth and elevated maternal blood pressure, reflecting preeclampsia-like phenotypes. Their offspring demonstrated a tendency toward excessive weight gain and delayed neurodevelopment. Overall, this study emphasizes the essential role of IL-18 in placental formation and its wider implications for fetomaternal health. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/649615v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@27862eorg.highwire.dtl.DTLVardef@da4786org.highwire.dtl.DTLVardef@8dd7e2org.highwire.dtl.DTLVardef@584c41_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISmooth muscle cells in the pregnant uterine myometrium sufficiently produce IL-18 C_LIO_LIIL-18 induces type 1 immune responses in the uterine immune milieu C_LIO_LIIL-18 promotes maternal uterine vascular remodeling and placental angiogenesis C_LIO_LIIL-18-signaling deficiency in the mouse model shows the preeclampsia-like clinical course C_LI