IL11 activates the placental inflammasome to drive preeclampsia

Front Immunol. 2023 May 24:14:1175926. doi: 10.3389/fimmu.2023.1175926. eCollection 2023.

Abstract

Introduction: 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.

Method: 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 1st trimester placental villi were treated with IL11 and the effect on inflammasome activation and pyroptosis identified by immunohistochemistry and ELISA.

Result: 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.

Discussion: Inhibition of ASC/NLRP3 inflammasome activity could prevent IL11-induced inflammation and fibrosis in various disease states including preeclampsia.

Keywords: ASC; NLRP3; fibrosis; hypertension; inflammasome; interleukin 11; preeclampsia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Fetal Growth Retardation / metabolism
  • Fibrosis
  • Humans
  • Hypertension*
  • Inflammasomes / metabolism
  • Inflammation / metabolism
  • Interleukin-11 / metabolism
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Placenta / metabolism
  • Placentation
  • Pre-Eclampsia* / metabolism
  • Pregnancy

Substances

  • Inflammasomes
  • Interleukin-11
  • NLR Family, Pyrin Domain-Containing 3 Protein

Grants and funding

This work was supported by the NHMRC (Australia) Project/Program Grant (GNT1098332) and Fellowships (#550905 to ED, 11594548 to K-AC), a University of Melbourne Department of Obstetrics and Gynecology Mid-career Fellowship and Innovation Grant to EM and the Victorian Government’s Operational Infrastructure Support. The funders were not involved in the conduct of research, preparation of the manuscript, or the decision to publish.