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Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Preeclampsia is a life-threatening disorder of pregnancy unique to humans. Interleukin (IL)11 is elevated in serum from pregnancies that subsequently develop early-onset preeclampsia and pharmacological elevation of IL11 in pregnant mice causes the development of early-onset preeclampsia-like features (hypertension, proteinuria, and fetal growth restriction). However, the mechanism by which IL11 drives preeclampsia is unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>Pregnant mice were administered PEGylated (PEG)IL11 or control (PEG) from embryonic day (E)10-16 and the effect on inflammasome activation, systolic blood pressure (during gestation and at 50\/90 days post-natal), placental development, and fetal\/post-natal pup growth measured. RNAseq analysis was performed on E13 placenta. Human 1<jats:sup>st<\/jats:sup> trimester placental villi were treated with IL11 and the effect on inflammasome activation and pyroptosis identified by immunohistochemistry and ELISA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Result<\/jats:title><jats:p>PEGIL11 activated the placental inflammasome causing inflammation, fibrosis, and acute and chronic hypertension in wild-type mice. Global and placental-specific loss of the inflammasome adaptor protein Asc and global loss of the Nlrp3 sensor protein prevented PEGIL11-induced fibrosis and hypertension in mice but did not prevent PEGIL11-induced fetal growth restriction or stillbirths. RNA-sequencing and histology identified that PEGIL11 inhibited trophoblast differentiation towards spongiotrophoblast and syncytiotrophoblast lineages in mice and extravillous trophoblast lineages in human placental villi. <\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Inhibition of ASC\/NLRP3 inflammasome activity could prevent IL11-induced inflammation and fibrosis in various disease states including preeclampsia.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1175926","type":"journal-article","created":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T05:33:15Z","timestamp":1684906395000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["IL11 activates the placental inflammasome to drive 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