IL11 activates the placental inflammasome to drive preeclampsia

Frontiers in Immunology

Immunology

Paddy Moore¹  Michelle Williams²  Ashley Mansell³  Katarzyna E. Rainczuk⁴  Amy L. Winship⁵  Kim-Anh Lê Cao⁶  Philana Nguyen⁷  Wei Zhou⁷  Leilani L. Santos⁷  Ellen Menkhorst⁸  Evdokia Dimitriadis⁹  Guannan Yang^1,10  Jian-Guo Zhang^1,11 

[1] Abortion and Contraception, Royal Women’s Hospital, Parkville, VIC, Australia;Biomedical Animal Facility, The University of Melbourne, Parkville, VIC, Australia;Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia;Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC, Australia;Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC, Australia;Department of Anatomy and Developmental Biology, Development and Stem Cells Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia;Department of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, Australia;Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, VIC, Australia;Gynaecology Research Centre, Royal Women’s Hospital, Parkville, VIC, Australia;Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, VIC, Australia;Gynaecology Research Centre, Royal Women’s Hospital, Parkville, VIC, Australia;Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC, Australia;Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, VIC, Australia;Gynaecology Research Centre, Royal Women’s Hospital, Parkville, VIC, Australia;Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC, Australia;Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia;Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, VIC, Australia;Gynaecology Research Centre, Royal Women’s Hospital, Parkville, VIC, Australia;Department of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, Australia;Walter and Eliza Hall Institute, Parkville, VIC, Australia;Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia;

关键词: interleukin 11;    preeclampsia;    ASC;    NLRP3;    inflammasome;    hypertension;    fibrosis;   

DOI  :  10.3389/fimmu.2023.1175926

 received in 2023-02-28, accepted in 2023-05-09,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionPreeclampsia 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.MethodPregnant 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 1st trimester placental villi were treated with IL11 and the effect on inflammasome activation and pyroptosis identified by immunohistochemistry and ELISA.ResultPEGIL11 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. DiscussionInhibition of ASC/NLRP3 inflammasome activity could prevent IL11-induced inflammation and fibrosis in various disease states including preeclampsia.

【 授权许可】

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Copyright © 2023 Menkhorst, Santos, Zhou, Yang, Winship, Rainczuk, Nguyen, Zhang, Moore, Williams, Lê Cao, Mansell and Dimitriadis