Loss of polarity regulators initiates gasdermin-E-mediated pyroptosis in syncytiotrophoblasts
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Published:2023-07-19
Issue:10
Volume:6
Page:e202301946
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ISSN:2575-1077
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Container-title:Life Science Alliance
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language:en
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Short-container-title:Life Sci. Alliance
Author:
Patel Khushali1,
Nguyen Jasmine2ORCID,
Shaha Sumaiyah2ORCID,
Brightwell Amy2,
Duan Wendy2ORCID,
Zubkowski Ashley3ORCID,
Domingo Ivan K1,
Riddell Meghan21ORCID
Affiliation:
1. Department of Obstetrics and Gynecology, University of Alberta
2. Department of Physiology, University of Alberta
3. Department of Biological Sciences, University of Alberta
Abstract
The syncytiotrophoblast is a human epithelial cell that is bathed in maternal blood on the maternal-facing surface of the human placenta. It therefore acts as a barrier and exchange interface between the mother and fetus. Syncytiotrophoblast dysfunction is a feature of pregnancy pathologies, like preeclampsia. Dysfunctional syncytiotrophoblasts display a loss of microvilli, which is a marker of aberrant apical–basal polarization, but little data exist about the regulation of syncytiotrophoblast polarity. Atypical PKC isoforms are conserved polarity regulators. Thus, we hypothesized that aPKC isoforms regulate syncytiotrophoblast polarity. Using human placental explant culture and primary trophoblasts, we found that loss of aPKC activity or expression induces syncytiotrophoblast gasdermin-E-dependent pyroptosis, a form of programmed necrosis. We also establish that TNF-α induces an isoform-specific decrease in aPKC expression and gasdermin-E-dependent pyroptosis. Therefore, aPKCs are homeostatic regulators of the syncytiotrophoblast function and a pathogenically relevant pro-inflammatory cytokine leads to the induction of programmed necrosis at the maternal–fetal interface. Hence, our results have important implications for the pathobiology of placental disorders like preeclampsia.
Funder
Gouvernement du Canada | Canadian Institutes of Health Research
Women and Children’s Health Research Institute
MaTCH Program
Alberta-Innovates Graduate Studentship
Women and Children’s Health Research Institute, Alberta-Innovates, and NSERC
Publisher
Life Science Alliance, LLC
Subject
Health, Toxicology and Mutagenesis,Plant Science,Biochemistry, Genetics and Molecular Biology (miscellaneous),Ecology