[Summery]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 distinctive 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 excessive cytotoxicity of uterine NK cells, 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.[Deposited dataset]We have deposited the raw, uncropped Western blot data prior to cropping. Each .zip archive is labeled to match the corresponding figure name in the manuscript.-Ino_et_al_Figure1.zip--1A_NLRP3_WB.tiff--1A_GAPDH_WB.tiff--1A_Caspase1_WB.tiff--1A_IL-18_WB.tiff--1A_Summery_WB.tif-Ino_et_al_FigureS1.zip--S1A_Caspase11_WB.tiff--S1A_GasderminD_WB.tiff--S1A_Caspase8_WB.tiff--S1A_GAPDH_WB.tiff--S1A_Summery_WB.tif

[Summery]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 distinctive 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 excessive cytotoxicity of uterine NK cells, 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.[Deposited dataset]We have deposited the raw, uncropped Western blot data prior to cropping. Each .zip archive is labeled to match the corresponding figure name in the manuscript.-Ino_et_al_Figure1.zip--1A_NLRP3_WB.tiff--1A_GAPDH_WB.tiff--1A_Caspase1_WB.tiff--1A_IL-18_WB.tiff--1A_Summery_WB.tif-Ino_et_al_FigureS1.zip--S1A_Caspase11_WB.tiff--S1A_GasderminD_WB.tiff--S1A_Caspase8_WB.tiff--S1A_GAPDH_WB.tiff--S1A_Summery_WB.tif