Dataset Information

The NLRP3 Inflammasome Role in the Pathogenesis of Pregnancy Induced Hypertension and Preeclampsia.

ABSTRACT: Pregnancy-induced hypertension and preeclampsia are associated with significant maternal and fetal mortality. A better understanding of these diseases, delineation of molecular pathomechanism, and efficient treatment development are some of the most urgent tasks in obstetrics and gynecology. Recent findings indicate the crucial role of inflammation in the development of hypertension and preeclampsia. Although the mechanism is very complex and needs further explanation, it appears that high levels of cholesterol, urate, and glucose activates NLRP3 inflammasome, which produces IL-1?, IL-18, and gasdermin D. Production of these proinflammatory chemokines is the beginning of a local and general inflammation, which results in sympathetic outflow, angiotensin II production, proteinuria, hemolysis, liver damage, immunothrombosis, and coagulopathy. The NLRP3 inflammasome is a critical complex in the mediation of the inflammatory response, which makes it crucial for the development of pregnancy-induced hypertension and preeclampsia, as well as its complications, such as placental abruption and HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Herein, the presented article delineates molecular mechanisms of these processes, indicating directions of future advance.

SUBMITTER: Socha MW

PROVIDER: S-EPMC7407205 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The NLRP3 Inflammasome Role in the Pathogenesis of Pregnancy Induced Hypertension and Preeclampsia.

Socha Maciej W MW Malinowski Bartosz B Puk Oskar O Dubiel Mariusz M Wiciński Michał M

Cells 20200708 7

Pregnancy-induced hypertension and preeclampsia are associated with significant maternal and fetal mortality. A better understanding of these diseases, delineation of molecular pathomechanism, and efficient treatment development are some of the most urgent tasks in obstetrics and gynecology. Recent findings indicate the crucial role of inflammation in the development of hypertension and preeclampsia. Although the mechanism is very complex and needs further explanation, it appears that high level ...[more]

PMID: 32650532

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Project description:BackgroundListeria monocytogenes (LM), a foodborne pathogen, can cause pregnancy failure in animals, especially in ruminants. Recent studies have shown that LM activates inflammasomes to induce IL-1β release in macrophages, however, whether the inflammasome activation regulates LM-induced pregnancy failure remains largely unknown. Here we used mouse model to investigate the molecular mechanism by which LM-induced inflammsome activation contributes to LM-associated pregnancy failureResultsWe showed that wild-type, but not Listeriolysin O-deficient (Δhly) LM, significantly reduced mouse embryo survival, accompanied by the increase of IL-1β release and caspase-1 activation. IL-1β neutralization significantly reduced the LM-induced embryo losses, suggesting that LM-induced pregnancy failure was associated with LLO-induced inflammasome activation. To dissect the inflammasome sensor and components responsible for LM-induced caspase-1 activation and IL-1β production, we used wild-type and NLRP3(-/-), AIM2(-/-), NLRC4(-/-), ASC(-/-), caspase-1(-/-) and cathepsin B(-/-) mouse macrophages to test the roles of these molecules in LM-induce IL-1β production. We found that NLRP3 inflammasome was the main pathway in LM-induced caspase-1 activation and IL-1β production. To explore the mechanism of LM-induced pregnancy failure, we investigated the effects of LM-infected macrophages on SM9-1 mouse trophoblasts. We found that the conditioned medium from LM-infected-macrophage or the recombinant IL-1β significantly up-regulated TNFα, IL-6 and IL-8 productions in trophoblasts, suggesting that the LM-induced macrophage inflammasome activation increased trophoblast pro-inflammatory cytokine production, which was adverse to the animal pregnancy maintenance.ConclusionsOur data demonstrated that the LLO-induced NLRP3 inflammasome activation plays a key role in LM-induced pregnancy failure, and inflammasome-mediated macrophage dysregulation on trophoblasts might be involved in the pregnancy failure.

Project description:Preeclampsia (PE) is a specific syndrome of pregnancy, characterized by hypertension and proteinuria. This pathology is associated with hyperuricemia and elevated serum levels of inflammatory cytokines. Uric acid crystals may activate an intracellular complex called inflammasome, which is important for processing and release of inflammatory cytokines. This study investigated the state of monocyte activation, both endogenous and stimulated with monosodium urate (MSU), by gene expression of NLRP1 and NLRP3 receptors as well as their association with inflammatory cytokines expression. Monocytes were obtained from peripheral blood of 23 preeclamptic pregnant women, 23 normotensive pregnant women (NT) and 23 healthy non-pregnant women (NP). Inflammasome activation was evaluated by the gene expression of NLRP1, NLRP3, caspase-1, IL-1β, IL-18 and TNF-α by RT-qPCR in unstimulated monocytes (endogenous expression), or after cell stimulation with MSU (stimulated expression). The concentration of cytokines was assessed by ELISA. In preeclamptic pregnant women, gene expression of NLRP1, NLRP3, caspase-1, IL-1β and TNF-α by monocytes stimulated or not with MSU was significantly higher than in NT and NP groups. Stimulation of monocytes from preeclamptic and non-pregnant women with MSU induced increased gene expression of NLRP3, caspase-1 and TNF-α in relation to the endogenous expression in these groups, while this was not observed in the NT group. The cytokine determination showed that monocytes from women with PE produced higher endogenous levels of IL-1β, IL-18 and TNF-α compared to the other groups, while the stimulus with MSU led to higher production of these cytokines in preeclamptic group than in the NT group. In conclusion, the results showed increased basal gene expression of NLRP1 and NLRP3 receptors in monocytes from PE group. These cells stimulation with MSU demonstrates that uric acid plays a role in NLRP3 inflammasome activation, suggesting the participation of this inflammatory complex in the pathogenesis of preeclampsia.

Dataset Information

The NLRP3 Inflammasome Role in the Pathogenesis of Pregnancy Induced Hypertension and Preeclampsia.

Publications

The NLRP3 Inflammasome Role in the Pathogenesis of Pregnancy Induced Hypertension and Preeclampsia.

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