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

Shi-Bin Cheng,Yoel Sadovsky,Warren J Huber,Sayani Banerjee,Zheping Huang,Shigeru Saito,Akitoshi Nakashima,Surendra Sharma,Sarah Davis

doi:10.1038/s41419-019-2162-4

Abstract

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.

Highlights

Preeclampsia (PE) is a multifactorial human pregnancy syndrome characterized by de novo onset of hypertension after 20 weeks of gestation with subtypes of early and late onset diagnosis[1,2,3,4,5,6]
We propose that placental pyroptosis is a major sterile inflammatory pathway in early onset PE (e-PE) that may lead to production of causative factors such as IL-1β and IL-18, which cause inflammation and potentiate the systemic manifestation of the syndrome
A small increase was noticed in NT-gasdermin D (GSDMD) in late onset PE (l-PE) samples, but this increase was not statistically significant when compared with e-PE placental samples from multiple deliveries (Fig. 1a; Supplementary Fig. 1a, b)

Summary

Introduction

Preeclampsia (PE) is a multifactorial human pregnancy syndrome characterized by de novo onset of hypertension after 20 weeks of gestation with subtypes of early (delivered before 34 weeks) and late onset (delivered after34 weeks) diagnosis[1,2,3,4,5,6]. DNA, toxic protein aggregates, and uric acid) into the maternal circulation[5,13,14,15,16,17,18,19,20]. These released factors and alarmins can elicit oxidative stress, systemic inflammation, and endothelial dysfunction as part of the composite PE manifestation profile[17,18]. The tissue origin and the pathways that contribute to circulating alarmins and inflammatory cytokines in PE patients remain poorly understood

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Conclusion