Inflammasome activation in preeclampsia and intrauterine growth restriction

Silber, Michal; Dekel, Nadav; Heusler, Ishai; Biron‐Shental, Tal; Amiel, Aliza; Kidron, Debora; Weisz, Avivit; Benchetrit, Sydney; Zitman‐Gal, Tali

doi:10.1111/aji.13598

Cited by 10 publications

(6 citation statements)

References 35 publications

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“…Inflammasome activation and its associated pro-inflammatory cascade are elevated in pre-eclampsia 182,183 . Inflammasomes are innate immune system receptors and sensors comprised of multimeric proteins that regulate the activation of caspase 1 and induce inflammation in response to infectious microbes and molecules derived from host proteins (called sterile inflammation) 184 .…”

Section: Dysregulated Placental Release Of Factorsmentioning

confidence: 99%

“…Inflammasomes are innate immune system receptors and sensors comprised of multimeric proteins that regulate the activation of caspase 1 and induce inflammation in response to infectious microbes and molecules derived from host proteins (called sterile inflammation) 184 . The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) and NLRP7 and their associated adaptor protein PYCARD are elevated in placenta and blood of women with pre-eclampsia 182,183 . There are several strategies being developed to inhibit inflammasome activation 185 that may be useful to treat inflammation-related pathways in pre-eclampsia.…”

Section: Dysregulated Placental Release Of Factorsmentioning

confidence: 99%

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Pre-eclampsia

Dimitriadis

Rolnik

Zhou

et al. 2023

Nat Rev Dis Primers

272

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Pre-eclampsia is a life-threatening disease of pregnancy unique to humans and a leading cause of maternal and neonatal morbidity and mortality. Women who survive pre-eclampsia have reduced life expectancy, with increased risks of stroke, cardiovascular disease and diabetes, while babies from a pre-eclamptic pregnancy have increased risks of preterm birth, perinatal death and neurodevelopmental disability and cardiovascular and metabolic disease later in life. Preeclampsia is a complex multisystem disease, diagnosed by sudden-onset hypertension (>20 weeks of gestation) and at least one other associated complication, including proteinuria, maternal organ dysfunction or uteroplacental dysfunction. Pre-eclampsia is found only when a placenta is or was recently present and is classified as preterm (delivery <37 weeks of gestation), term (delivery ≥37 weeks of gestation) and postpartum pre-eclampsia. The maternal syndrome of pre-eclampsia is driven by a dysfunctional placenta, which releases factors into maternal blood causing systemic inflammation and widespread maternal endothelial dysfunction. Available treatments target maternal hypertension and seizures, but the only 'cure' for pre-eclampsia is delivery of the dysfunctional placenta and baby, often prematurely. Despite decades of research, the aetiology of pre-eclampsia, particularly of term and postpartum pre-eclampsia, remains poorly defined. Significant advances have been made in the prediction and prevention of preterm pre-eclampsia, which is predicted in early pregnancy through combined screening and is prevented with daily low-dose aspirin, starting before 16 weeks of gestation. By contrast, the prediction of term and postpartum pre-eclampsia is limited and there are no preventive treatments. Future research must investigate the pathogenesis of pre-eclampsia, in particular of term and postpartum pre-eclampsia, and evaluate new Nature Reviews Disease Primers | (2023) 9:8 2 0123456789();: Primer Epidemiology Incidence and mortalityThe global prevalence of all pre-eclampsia in the years 2002-2010 was estimated at 4.6% of deliveries but reported regional rates varied between 1% and 5.6% 14 . Where reported, the prevalence of preterm pre-eclampsia is <1% [15][16][17][18] . The prevalence of pre-eclampsia is generally reported as lower in low-income and middle-income countries (LMICs) (except sub-Saharan Africa) than in high-income countries (HICs) 19,20 ; however, it is likely that differences in classification, access to prenatal care and under-reporting in LMICs affect prevalence data 20,21 . Furthermore, most pre-eclampsia research is performed in HICs, potentially leading to bias and generalizability concerns in the populations sampled and the research questions asked.Hypertensive disorders of pregnancy (including pre-eclampsia) are the second most common cause (behind haemorrhage) of maternal Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rights...

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Section: Dysregulated Placental Release Of Factorsmentioning

confidence: 99%

Section: Dysregulated Placental Release Of Factorsmentioning

confidence: 99%

Pre-eclampsia

Dimitriadis

Rolnik

Zhou

et al. 2023

Nat Rev Dis Primers

272

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“…Placental villus explants release highly variable levels of IL1β (and IL18) under control conditions due to constitutive NLRP3 inflammasome activity – without detectable Gasdermin D cleavage ( 48 ), suggesting that constitutive placental inflammasome activity is critical for healthy placental function. However, preeclamptic placentas secrete higher levels of IL1β into the maternal circulation ( 49 ) and key components of the inflammasome including ASC, cleaved caspase-1, GSDMD NT , and HMGB1 are increased in the placenta from women with preeclampsia ( 22 , 24 , 50 ). Our in vitro data shows that IL11-induced activation of the inflammasome in the human placental villus results in Gasdermin D cleavage and pyroptotic cell death, thus placental exposure to excess IL11 may cause hyperactivation of the placental inflammasome, resulting in Gasdermin D cleavage, pyroptotic cell death, and placental damage leading to preeclampsia.…”

Section: Discussionmentioning

confidence: 99%

“…There is emerging evidence for elevated placental inflammasome activation in early-onset preeclampsia ( 1 , 22 – 24 ); thus, we hypothesized that IL11 would activate placental inflammasomes resulting in cleaved IL1β, pyroptosis, and initiation of the cascade of events leading to preeclampsia. We aimed to determine the effects of IL11 on inflammasome activation in human and mouse placenta and whether loss of NLRP3/ASC-inflammasome activity could prevent IL11-induced preeclampsia.…”

Section: Introductionmentioning

confidence: 99%

IL11 activates the placental inflammasome to drive preeclampsia

et al. 2023

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IntroductionPreeclampsia is a life-threatening disorder of pregnancy unique to humans. Interleukin (IL)11 is elevated in serum from pregnancies that subsequently develop early-onset preeclampsia and pharmacological elevation of IL11 in pregnant mice causes the development of early-onset preeclampsia-like features (hypertension, proteinuria, and fetal growth restriction). However, the mechanism by which IL11 drives preeclampsia is unknown.MethodPregnant mice were administered PEGylated (PEG)IL11 or control (PEG) from embryonic day (E)10-16 and the effect on inflammasome activation, systolic blood pressure (during gestation and at 50/90 days post-natal), placental development, and fetal/post-natal pup growth measured. RNAseq analysis was performed on E13 placenta. Human 1st trimester placental villi were treated with IL11 and the effect on inflammasome activation and pyroptosis identified by immunohistochemistry and ELISA.ResultPEGIL11 activated the placental inflammasome causing inflammation, fibrosis, and acute and chronic hypertension in wild-type mice. Global and placental-specific loss of the inflammasome adaptor protein Asc and global loss of the Nlrp3 sensor protein prevented PEGIL11-induced fibrosis and hypertension in mice but did not prevent PEGIL11-induced fetal growth restriction or stillbirths. RNA-sequencing and histology identified that PEGIL11 inhibited trophoblast differentiation towards spongiotrophoblast and syncytiotrophoblast lineages in mice and extravillous trophoblast lineages in human placental villi. DiscussionInhibition of ASC/NLRP3 inflammasome activity could prevent IL11-induced inflammation and fibrosis in various disease states including preeclampsia.

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“…In the evaluation of the role of the inflammatory process in PE development, trophoblast-derived extracellular vesicles from PE women were found to promote PE by inducing macrophage imbalance polarization from M2 to M1 phenotype with significant upregulation of M1 gene markers and downregulation of macrophage CD163 expression than in NT women, thus altering the classical inflammatory biological pathways in macrophages [25] . Another study found the placental tissue expression levels of the inflammatory proteins NLRP7 and PYCARD were higher in the placentas of PE versus NT samples and these proteins could be used as markers of prediction or progression of PE [26] . Another possible mechanism was the single nucleotide polymorphism (SNP) in TNF-α and interleukins-4, 6, 10, 17A, and 22 for the development of early-onset and severe PE [27] .…”

Section: Discussionmentioning

confidence: 99%

The Relation between Deregulated Immune Milieu and Atherogenic Lipids Might Underlie the Development of Pregnancy-induced Hypertensive Disorders

Zaher

Rageh

Morsy

2023

Evidence Based Women's Health Journal

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Objectives: Evaluation of the relation between plasma lipoprotein(a) (LPA) and serum tumor necrosis factor-α (TNF-α) levels estimated in blood samples (S1 sample) obtained at the 6th gestational week (GW; T1 time) and the development of preeclampsia (PE) as judged by blood pressure measures at the time of diagnosis of PE (T2 time). Patients and Methods: 140 newly pregnant women gave S1 sample at T1 time; during pregnancy 19 women developed early-onset PE (EOPE) and 51 women developed late-onset PE (LOPE); 16 women developed severe PE (SPE) and 54 women developed mild PE (MPE), while 70 women were normotensive (NT) till the end of pregnancy. At T2 time, all patients gave S2 sample for ELISA estimation of plasma LPA and serum TNF-α level in both samples. Results: Serum TNF-α and plasma LPA levels were significantly higher in all S2 than S1 samples, in both samples of PE than NT women, and in both samples of women who developed EOPE and/or SPE than in samples of women who developed LOPE and/or MPE, respectively. Regression analysis of T1 data defined high body mass index; BMI (β=0.162, P=0.028), high S1 levels of TNF-α (β=0.424, P<0.001), and LPA (β=0.314, P<0.001) as predictors for development of PE as judged by SBP measures at T2 time. Correlation analysis showed a positive significant (P<0.001) correlation between at-T2-SBP measures with at-T1 BMI and S1 levels of TNF-α and LPA with a positive significant correlation between levels of both variables and with at-T1 BMI. Conclusion: High serum levels of TNF-α and plasma LPA levels early in pregnancy could predict the development of PE and its severity.

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Inflammasome activation in preeclampsia and intrauterine growth restriction

Cited by 10 publications

References 35 publications

Pre-eclampsia

Pre-eclampsia

IL11 activates the placental inflammasome to drive preeclampsia

The Relation between Deregulated Immune Milieu and Atherogenic Lipids Might Underlie the Development of Pregnancy-induced Hypertensive Disorders

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