NLRP3 inflammasome as the potential target mechanism and therapy in recurrent spontaneous abortions

Lu, Mudan; Ma, Fang; Xiao, Jia; Yang, Lan; Li, Na; Chen, Daozhen

doi:10.3892/mmr.2019.9829

Cited by 8 publications

(4 citation statements)

References 51 publications

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“…NLRP3 expression is reported to have a role in mediating inflammation and vascular function in PE as well as other hypertensive disorders [21][22][23][24][25]. Previous work from our lab demonstrated that NLRP3 expression is elevated in the RUPP rat model of placental ischemia; we uncovered a cause-and-effect relationship between NLRP3 inflammasome activation and effector cell populations by inhibiting NLRP3 activation with MCC950 and esomeprazole [19].…”

Section: Discussionmentioning

confidence: 75%

Inhibition of Caspase 1 Reduces Blood Pressure, Cytotoxic NK Cells, and Inflammatory T-Helper 17 Cells in Placental Ischemic Rats

Shields,

Tardo,

Wang

et al. 2024

IJMS

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Preeclampsia (PE) is characterized by maternal hypertension, fetal growth restriction (FGR), and increased inflammation and populations of cytotoxic NK cells (cNKs) and inflammatory T-Helper 17 cells (TH17s). Both cytotoxic NK cells and TH17 cells are heavily influenced via IL-1β signaling. Caspase 1 activity leads to the release of the inflammatory cytokine IL-1β, which is increased in women with PE. Therefore, we tested the hypothesis that the inhibition of Caspase 1 with VX-765 in rats with reduced uterine perfusion pressure (RUPP) will attenuate PE pathophysiology. On gestation day (GD) 14, timed pregnant Sprague–Dawley rats underwent the RUPP or Sham procedure and were separated into groups that received either vehicle or VX-765 (50 mg/kg/day i.p.). On GD19, MAP was measured via carotid catheter and blood and tissues were collected. Bio-Plex and flow cytometry analysis were performed on placental tissues. Placental IL-1β was increased in the RUPP rats vs. the Sham rats and treatment with VX-765 reduced IL-1β in the RUPP rats. Caspase 1 inhibition reduced placental cNKs and TH17s in RUPP rats compared to vehicle-treated RUPP rats. Increased MAP was observed in RUPP rats compared with Sham rats and was reduced in RUPP + VX-765 rats. Placental reactive oxygen species (ROS) were elevated in RUPP rats compared to Sham rats. VX-765 administration reduced ROS in treated RUPP rats. Caspase 1 inhibition increased the number of live pups, yet had no effect on fetal weight or placental efficiency in the treated groups. In conclusion, Caspase 1 inhibition reduces placental IL-1β, inflammatory TH17 and cNK populations, and reduces MAP in RUPP rats. These data suggest that Caspase 1 is a key contributor to PE pathophysiology. This warrants further investigation of Caspase 1 as a potential therapeutic target to improve maternal outcomes in PE.

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Section: Discussionmentioning

confidence: 75%

Inhibition of Caspase 1 Reduces Blood Pressure, Cytotoxic NK Cells, and Inflammatory T-Helper 17 Cells in Placental Ischemic Rats

Shields,

Tardo,

Wang

et al. 2024

IJMS

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“…Furthermore, there is a negative correlation between NLRP3 expression levels and the frequency of circulating Treg cells in patients with recurrent spontaneous abortions [21].…”

Section: Introductionmentioning

confidence: 99%

Obeticholic acid treatment ameliorates the cardiac dysfunction in NASH mice

et al. 2022

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Background Suppression of cardiac iinflammasome, which can be inhibited by Farnesoid X receptor (FXR) agonist, can ameliorate cardiac inflammation and fibrosis. Increased cardiac inflammasome decrease the abundance of regulatory T (Treg) cells and exacerbate cardiac dysfunction. Interaction between cardiomyocytes and Treg cells is involved in the development of nonalcoholic steatohepatitis (NASH)-related cardiac dysfunction. Aims This study evaluates whether the FXR agonist obeticholic acid (OCA) treatment improves NASH-associated cardiac dysfunction. Methods The in vivo and in vitro mechanisms and effects of two weeks of OCA treatment on inflammasome and Treg dysregulation-related cardiac dysfunction in NASH mice (NASH-OCA) at systemic, tissue and cellular levels were investigated. Results The OCA treatment suppressed the serum and cardiac inflammasome levels, reduced the cardiac infiltrated CD3+ T cells, increased the cardiac Treg-represented anti-inflammatory cytokines (IL-10/IL-10R) and improved cardiac inflammation, fibrosis and function [decreased left ventricle (LV) mass and increased fractional shortening (FS)] in NASH-OCA mice. The percentages of OCA-decreased cardiac fibrosis and OCA-increased FS were positively correlated with the percentage of OCA-increased levels of cardiac FXR and IL-10/IL-10R. In the Treg cells from NASH-OCA mice spleen, in comparison with the Treg cells of the NASH group, higher intracellular FXR but lower inflammasome levels, and more proliferative/active and less apoptotic cells were observed. Incubation of H9c2 cardiomyoblasts with Treg-NASHcm [supernatant of Treg from NASH mice as condition medium (cm)], increased inflammasome levels, decreased the proliferative/active cells, suppressed the intracellular FXR, and downregulated differentiation/contraction marker. The Treg-NASHcm-induced hypocontractility of H9c2 can be attenuated by co-incubation with OCA, and the OCA-related effects were abolished by siIL-10R pretreatment. Conclusions Chronic FXR activation with OCA is a potential strategy for activating IL-10/IL-10R signalling, reversing cardiac regulatory T cell dysfunction, and improving inflammasome-mediated NASH-related cardiac dysfunction.

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“…Studies report increased NLRP3 expression in PE and other hypertensive and gestation disorders. Furthermore, it is proposed that NLRP3 activation plays a role in mediating the inflammatory and vascular changes associated with hypertension and recurrent spontaneous abortion [16][17][18][19][20]. Studies in various inflammatory diseases as well as our own work have suggested that NLRP3 activation disrupts IL-33 signaling to activate T H 17s and cNKs [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

IL‐33 Signaling Inhibition Leads to a Preeclampsia‐Like Phenotype in Pregnant Rats

Wang,

Shields,

Thompson

et al. 2024

American J Rep Immunol

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ProblemPreeclampsia (PE) is a hypertensive pregnancy disorder that is a leading cause of maternal and fetal morbidity and mortality characterized by maternal vascular dysfunction, oxidative stress, chronic immune activation, and excessive inflammation. No cure exists beyond delivery of the fetal–placental unit and the mechanisms driving pathophysiology are not fully understood. However, aberrant immune responses have been extensively characterized in clinical studies and shown to mediate PE pathophysiology in animal studies. One pathway that may mediate aberrant immune responses in PE is deficiencies in the IL‐33 signaling pathway. In this study, we aim to investigate the impact of IL‐33 signaling inhibition on cNK, TH17, and TReg populations, vascular function, and maternal blood pressure during pregnancy.Method of StudyIn this study, IL‐33 signaling was inhibited using two different methods: intraperitoneal administration of recombinant ST2 (which acts as a decoy receptor for IL‐33) and administration of a specific IL‐33 neutralizing antibody. Maternal blood pressure, uterine artery resistance index, renal and placental oxidative stress, cNK, TH17, and TReg populations, various cytokines, and pre‐proendothelin‐1 levels were measured.ResultsIL‐33 signaling inhibition increased maternal blood pressure, uterine artery resistance, placental and renal oxidative stress. IL‐33 signaling inhibition also increased placental cNK and TH17 and renal TH17 cells while decreasing placental TReg populations. IL‐33 neutralization increased circulating cNK and TH17s and decreased circulating TRegs in addition to increasing pre‐proendothelin‐1 levels.ConclusionsData presented in this study demonstrate a role for IL‐33 signaling in controlling vascular function and maternal blood pressure during pregnancy possibly by mediating innate and adaptive immune inflammatory responses, identifying the IL‐33 signaling pathway as a potential therapeutic target for managing preeclampsia.

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NLRP3 inflammasome as the potential target mechanism and therapy in recurrent spontaneous abortions

Cited by 8 publications

References 51 publications

Inhibition of Caspase 1 Reduces Blood Pressure, Cytotoxic NK Cells, and Inflammatory T-Helper 17 Cells in Placental Ischemic Rats

Inhibition of Caspase 1 Reduces Blood Pressure, Cytotoxic NK Cells, and Inflammatory T-Helper 17 Cells in Placental Ischemic Rats

Obeticholic acid treatment ameliorates the cardiac dysfunction in NASH mice

IL‐33 Signaling Inhibition Leads to a Preeclampsia‐Like Phenotype in Pregnant Rats

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