Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021

IL11 activates the placental inflammasome, causing pyroptosis and fibrosis and leading to preeclampsia. (#107)

Ellen Menkhorst 1 2 , Leilani Santos 1 2 , Wei Zhou 1 2 , Kate Rainczuk 3 , Amy Winship 4 , Jianguo Zhang 5 , Ashley Mansell 3 , Evdokia Dimitriadis 1 2
  1. The University of Melbourne, Parkville, VIC, Australia
  2. Gynecology Research Centre, Royal Women's Hospital, Parkville, VIC, Australia
  3. Hudson Institute of Medical Research, Clayton, VIC, Australia
  4. Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  5. Walter and Eliza Hall Institute, Parkville, VIC, Australia

Preeclampsia is a life-threatening disorder of pregnancy unique to humans, diagnosed by sudden onset hypertension (>20 weeks gestation) plus one other complication. Abnormal placental inflammasome activation is associated with preeclampsia, however the cause of excess placental inflammasome activity is unknown. Interleukin (IL)11 is elevated in 1st trimester maternal serum of pregnancies that subsequently develop early-onset preeclampsia. IL11 administration to pregnant mice recapitulates preeclampsia-like features (hypertension and proteinuria). We hypothesized IL11 activates placental inflammasomes to cause preeclampsia.

Pregnant female C57BL6J wild-type mice and mice which lack the inflammasome adaptor component ASC (ASC-/-) were subcutaneously injected with PEGylated (PEG)IL11 (500µg/kg/day) from embryonic day (E)10-16 (n=4-6/group) and systolic blood pressure (sBP), proteinuria, serum sFlt-1, placental formation, fetal/pup growth and placental/renal inflammasome activation measured. Human 1st trimester placental villous explants (n=6-9/group) were treated with IL11 (100ng/ml) +/- MCC950 (5µM, NLRP3 inflammasome inhibitor) for 72h and inflammasome activation measured.

PEGIL11 treatment caused preeclampsia-like features (hypertension, proteinuria), activated placental and renal inflammasomes (cleaved caspase-1, IL1β, gasdermin-D) and caused placental and renal fibrosis only in wild-type mice: no effect was seen in ASC-/- mice. However, preventing PEGIL11-induced placental inflammasome activation did not ameliorate PEGIL11-induced placental damage: PEGIL11 treatment impaired labyrinth trophoblast differentiation, elevated circulating sFlt-1 and caused fetal growth restriction and stillbirth in both wild-type and ASC-/- mice. In human placental villous, IL11 activated cytotrophoblast inflammasomes (caspase-1 cleavage, IL1β secretion) resulting in cytotrophoblast pyroptosis (cleaved gasdermin-D and LDH release), which was inhibited by MCC950 co-treatment.

For the first time we demonstrated that IL11 activates the inflammasome, causing trophoblast pyroptosis and placental and renal fibrosis. Inhibition of placental/renal inflammasome activation prevented the maternal symptoms of preeclampsia. However, as IL11-induced placental damage was not ameliorated by loss of ASC, inhibition of inflammasome activity in the placenta without inhibition of other IL11 signaling pathways may not prevent adverse fetal outcomes.