E-Poster Presentation ESA-SRB-ANZBMS 2021

Temporal expression of inflammasomes is increased in human placentae affected by fetal growth restriction (FGR),  and in three inflammation-induced models of FGR: a murine model in vivo; human placental organoids and cultured BeWo cells in vitro. (#561)

Padma Murthi 1 2 3 , Amlan Chakraborty 3 , Irvan Alfian 3 , Georgia Sgroi 3 , Sheetal Saini 3 , Bill Kalionis 1 , Chrishan Samuel 3 , Evdokia Dimitriadis 2 , Nadia Alfaidy 4 , Sharon Ricardo 3 , Shaun Brennecke 1 2
  1. Maternal Fetal Medicine, Pregnancy Research Centre, Royal Women's Hospital, Parkville, Victoria, Australia
  2. Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia
  3. Monash University, Clayton, VIC, Australia
  4. Institut National de la Santé et de la Recherche Médicale, Inserm U1292, Biosanté, University Grenoble-Alpes, Grenoble, France

Background: Fetal growth restriction (FGR) is defined as a birth weight of <10th centile for gestational age, with severe FGR (<3rd centile) contributing significantly to stillbirth and iatrogenic preterm birth. The primary cause of FGR is placental insufficiency. The human placenta is immunologically active through trophoblasts, which generate specific and diverse innate-immune responses through the expression of multimeric self-assembling protein complexes, called inflammasomes. However, changes in expression levels of inflammasomes in the placentae of FGR are poorly understood.

Hypothesis: Placental inflammasome component expression is increased in human FGR tissues, in an inflammation-induced murine pregnancy in vivo, in an in vitro human placental organoid model system, and in the trophoblast-derived cell line model, BeWo.  

Methods: Human placentae from third trimester idiopathic FGR (n=25) and gestation-matched uncomplicated control pregnancies (n=25, 28-40 weeks of gestation) were collected to determine the expression of the inflammasome components using a Fluidigm BiomarkTM array, with independent validation by real-time PCR. Candidate inflammasome component expression was investigated in placentae following lipopolysaccharide treatment to induce inflammation in 1) a murine model in vivo, 2) an in vitro cultured 3-D self-organising human placental organoids generated from 6-9 weeks of gestation, and 3) in cultured BeWos.  

Results: Placental mRNA expression for the inflammasome components NLRP3, NLRC5, CASP1, NFκB1, IFNγ, IL-1β and IL-6, was significantly increased relative to 18S rRNA, while the anti-inflammatory cytokine, IL-10 mRNA expression was significantly decreased in human FGR compared with control pregnancies (p<0.001). NLRP3 correlated with gestational age in human FGR (r=0.558, p=0.004). NLRP3 protein expression was increased in LPS-induced inflammation in the murine placentae,  in vitro models of human placental organoid system and BeWos.

Conclusion: Placental expression of inflammasomes components was associated with increased pro-inflammatory cytokine expression in FGR. Further functional analysis may identify inflammasomes as potential biomarkers of pregnancies at risk of developing FGR.