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

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.

Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer

“…These inflammasomes recruit adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) to activate caspase1 [41]. Caspase1 can cleave GSDMD to generate the N-terminal domain of GSDMD (GSDMD-N), which permeabilizes the plasma membrane, undergoing pyroptosis [18,[42][43][44]. GSDMD has been widely characterized for its ability to form necrotic pores in the plasma membrane.…”

“…Exposure to hypoxia induces excessive endoplasmic reticulum and unfolded protein response to enhance the NLRP3 inflammatory pathway through thioredoxin-interacting protein (TXNIP) and activate caspase1/GSDMD-mediated pyroptosis in primary human trophoblasts. Resveratrol, a TXNIP inhibitor, decreases the expression of NLRP3 and caspase1 to contribute to therapy of early onset preeclampsia pathology [18]. Clinically, high glucose activates pyroptosis through the caspase1/GSDMD/IL-1β pathway to release proinflammatory cytokines, repressing the proliferation and differentiation of osteoblast in alveolar bone, and Ac-YVAD-CMK, a caspase1 inhibitor, can reverse expression of these proteins and attenuate the formation of periodontal diseases [62].…”

“…However, the long-term exposure of normal tissues to the inflammatory environment may increase the risk of cancers (such as colorectal cancer) [9,15]. It is needed to explore the effect of the blockage of pyroptosis for treating inflammatory factors-driven disease [17,18]. On the other hand, resisting cell death is the important hallmark of cancers [19].…”

The Inflammasome in Reproductive Biology: A Promising Target for Novel Therapies

“…To this extent, a recent article has been published showing that hypoxia and endoplasmic reticulum stress activate the NLRP3 inflammasome in primary human trophoblasts, resulting in increased expression of Thioredoxin-interacting protein (TXNIP), a key regulator of inflammasome activation (51). Moreover, these findings were consistent with increased cleavage of caspase-1 and GSDM-D, thus indicating that placental pyroptosis contributes to the systemic release of factors involved in preeclampsia (52).…”

Dopamine Reduced Pyroptosis and Improved Functional Recovery After Spinal Cord Injury 

“…During injury of the central nervous system, caspase-1 cleaves GSDMD to generate the N-terminal fragment of GSDMD [14,15]. This leads to rupture of the cellular membrane and the release of cellular contents, including the proin ammatory cytokines interleukin (IL)-1β and IL-18 [16]. Pyroptosis contributes to neuronal loss in traumatic brain injury [17], SCI [18], and demyelination in multiple sclerosis [19].…”