The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction
Irvan Alfian,
Amlan Chakraborty,
Hannah E. J. Yong,
Sheetal Saini,
Ricky W. K. Lau,
Bill Kalionis,
Evdokia Dimitriadis,
Nadia Alfaidy,
Sharon D. Ricardo,
Chrishan S. Samuel,
Padma Murthi
Affiliations
Irvan Alfian
Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Amlan Chakraborty
Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Hannah E. J. Yong
Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore 117609, Singapore
Sheetal Saini
Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Ricky W. K. Lau
Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Bill Kalionis
Department of Maternal-Fetal Medicine Pregnancy Research Centre, The Royal Women’s Hospital, Melbourne, VIC 3052, Australia
Evdokia Dimitriadis
Department of Obstetrics and Gynaecology, The University of Melbourne, Melbourne, VIC 3052, Australia
Nadia Alfaidy
Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38043 Grenoble, France
Sharon D. Ricardo
Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Chrishan S. Samuel
Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Padma Murthi
Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Fetal growth restriction (FGR) is commonly associated with placental insufficiency and inflammation. Nonetheless, the role played by inflammasomes in the pathogenesis of FGR is poorly understood. We hypothesised that placental inflammasomes are differentially expressed and contribute to the aberrant trophoblast function. Inflammasome gene expression profiles were characterised by real-time PCR on human placental tissues collected from third trimester FGR and gestation-matched control pregnancies (n = 25/group). The functional significance of a candidate inflammasome was then investigated using lipopolysaccharide (LPS)-induced models of inflammation in human trophoblast organoids, BeWo cells in vitro, and a murine model of FGR in vivo. Placental mRNA expression of NLRP3, caspases 1, 3, and 8, and interleukin 6 increased (>2-fold), while that of the anti-inflammatory cytokine, IL-10, decreased (2-fold) in trophoblast organoids and BeWo cell cultures in vitro, and in the spongiotrophoblast and labyrinth in the murine model of FGR. However, the LPS-induced rise in NLRP3 was attenuated by its siRNA-induced down-regulation in BeWo cell cultures, which correlated with reduced activity of the apoptotic markers, caspase-3 and 8, compared to the control siRNA-treated cells. Our findings support the role of the NLRP3 inflammasome in the inflammation-induced aberrant trophoblast function, which may contribute to FGR.
