Pyroptosis is a critical inflammatory pathway in the placenta from early onset preeclampsia and in human trophoblasts exposed to hypoxia and endoplasmic reticulum stressors

• Published in: Cell death & disease Vol. 10; no. 12; pp. 927 - 15
• Main Authors: Cheng, Shi-Bin, Nakashima, Akitoshi, Huber, Warren J., Davis, Sarah, Banerjee, Sayani, Huang, Zheping, Saito, Shigeru, Sadovsky, Yoel, Sharma, Surendra
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.12.2019; Springer Nature B.V
• Subjects: 13; 13/106; 13/51; 14; 14/19; 631/80/304; 692/420/256/2177; 82; 82/1; 82/29; 96; 96/1; 96/95; Adult; Antibodies; Autophagy; Biochemistry; Biomedical and Life Sciences; Carrier Proteins - genetics; Caspase-1; Cell Biology; Cell Culture; Cell death; Cell Hypoxia - genetics; Endoplasmic reticulum; Endoplasmic Reticulum Stress - genetics; Female; Humans; Hypoxia; IL-1β; Immunology; Inflammasomes; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Interleukin 18; Intracellular Signaling Peptides and Proteins - genetics; Life Sciences; Mimicry; Necroptosis; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; Phagocytosis; Phosphate-Binding Proteins - genetics; Placenta; Placenta - metabolism; Placenta - pathology; Pre-eclampsia; Pre-Eclampsia - genetics; Pre-Eclampsia - metabolism; Pre-Eclampsia - pathology; Preeclampsia; Pregnancy; Protein folding; Pyrin protein; Pyroptosis; Pyroptosis - genetics; Signal Transduction; Thioredoxin; Trophoblasts; Trophoblasts - metabolism; Trophoblasts - pathology; Unfolded Protein Response - genetics
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-2162-4

Systemic manifestation of preeclampsia (PE) is associated with circulating factors, including inflammatory cytokines and damage-associated molecular patterns (DAMPs), or alarmins. However, it is unclear whether the placenta directly contributes to the increased levels of these inflammatory triggers. Here, we demonstrate that pyroptosis, a unique inflammatory cell death pathway, occurs in the placenta predominantly from early onset PE, as evidenced by elevated levels of active caspase-1 and its substrate or cleaved products, gasdermin D (GSDMD), IL-1β, and IL-18. Using cellular models mimicking pathophysiological conditions (e.g., autophagy deficiency, hypoxia, and endoplasmic reticulum (ER) stress), we observed that pyroptosis could be induced in autophagy-deficient human trophoblasts treated with sera from PE patients as well as in primary human trophoblasts exposed to hypoxia. Exposure to hypoxia elicits excessive unfolded protein response (UPR) and ER stress and activation of the NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome in primary human trophoblasts. Thioredoxin-interacting protein (TXNIP), a marker for hyperactivated UPR and a crucial signaling molecule linked to NLRP3 inflammasome activation, is significantly increased in hypoxia-treated trophoblasts. No evidence was observed for necroptosis-associated events. Importantly, these molecular events in hypoxia-treated human trophoblasts are significantly observed in placental tissue from women with early onset PE. Taken together, we propose that placental pyroptosis is a key event that induces the release of factors into maternal circulation that possibly contribute to severe sterile inflammation and early onset PE pathology.