Role of the NLRP3 Inflammasome in Preeclampsia

Shirasuna, Koumei; Karasawa, Tadayoshi; Takahashi, Masafumi

doi:10.3389/fendo.2020.00080

Cited by 76 publications

(60 citation statements)

References 172 publications

(209 reference statements)

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“…Preeclampsia without FGR was associated with increased decidual expression of NLRP3 and IL-1β, suggesting that the NLRP3 inflammasome aggravates the inflammatory response and substantiates the reported shift to a pro-inflammatory profile and cell type distribution at the maternal-fetal interface in preeclampsia ( 9 , 14 , 29 ). The increased decidual inflammasome expression was trophoblast dependent and strongest in areas where trophoblast and leukocytes are in proximity, suggesting that NLRP3 mediated inflammation may disturb maternal-fetal communication.…”

Section: Discussionsupporting

confidence: 76%

“…Preeclampsia is associated with increased maternal systemic inflammatory markers including total cholesterol, oxLDL, IL-1β and soluble fms-like tyrosine kinase-1 (sFlt-1) (26)(27)(28). The NLRP3 inflammasome pathway in preeclampsia has been recently reviewed and mechanistically illustrated (29). We have previously shown that the NLRP3 inflammasome is active in the placenta and associated with preeclampsia, with a central involvement of trophoblasts (28).…”

Section: Introductionmentioning

confidence: 99%

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Cholesterol Crystals and NLRP3 Mediated Inflammation in the Uterine Wall Decidua in Normal and Preeclamptic Pregnancies

et al. 2020

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Preeclampsia is a hypertensive and inflammatory pregnancy disorder associated with cholesterol accumulation and inflammation at the maternal-fetal interface. Preeclampsia can be complicated with fetal growth restriction (FGR) and shares risk factors and pathophysiological mechanisms with cardiovascular disease. Cholesterol crystal mediated NLRP3 inflammasome activation is central to cardiovascular disease and the pathway has been implicated in placental inflammation in preeclampsia. Direct maternal-fetal interaction occurs both in the uterine wall decidua and at the placental surface and these aligned sites constitute the maternal-fetal interface. This study aimed to investigate cholesterol crystal accumulation and NLRP3 inflammasome expression by maternal and fetal cells in the uterine wall decidua of normal and preeclamptic pregnancies. Pregnant women with normal ( n = 43) and preeclamptic pregnancies with ( n = 28) and without ( n = 19) FGR were included at delivery. Cholesterol crystals were imaged in decidual tissue by both second harmonic generation microscopy and polarization filter reflected light microscopy. Quantitative expression analysis of NLRP3, IL-1β and cell markers was performed by immunohistochemistry and automated image processing. Functional NLRP3 activation was assessed in cultured decidual explants. Cholesterol crystals were identified in decidual tissue, both in the tissue stroma and near uterine vessels. The cholesterol crystals in decidua varied between pregnancies in distribution and cluster size. Decidual expression of the inflammasome components NLRP3 and IL-1β was located to fetal trophoblasts and maternal leukocytes and was strongest in areas of proximity between these cell types. Pathway functionality was confirmed by cholesterol crystal activation of IL-1β in cultured decidual explants. Preeclampsia without FGR was associated with increased trophoblast dependent NLRP3 and IL-1β expression, particularly in the decidual areas of trophoblast and leukocyte proximity. Our findings suggest that decidual accumulation of cholesterol crystals may activate the NLRP3 inflammasome and contribute to decidual inflammation and that this pathway is strengthened in areas with close maternal-fetal interaction in preeclampsia without FGR.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Cholesterol Crystals and NLRP3 Mediated Inflammation in the Uterine Wall Decidua in Normal and Preeclamptic Pregnancies

et al. 2020

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“…This activation process spreads rapidly via paracrine and endocrine pathways to other nearby or distant endothelial cells [ 78 ]. As discussed above, these particles may act via intravesicular microRNAs and/or circular RNAs that, after phagocytosis by endothelial and immune cells, induce sterile inflammation and alter the production of mediators of angiogenesis and vasoactivity, such as sFLT1, VEGF, and pregnancy-associated placental protein A (PAPP-A) [ 61 , 62 , 80 ]. Many other vasoactive and immunological mediators have been studied in the maternal serum for the diagnosis or prediction of PE, and are summarized in Table 3 .…”

Section: Pathophysiologymentioning

confidence: 99%

Preeclampsia Is a Syndrome with a Cascade of Pathophysiologic Events

Gyselaers

2020

JCM

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This review integrates the currently available information on the molecular, cellular, and systemic mechanisms involved in the pathophysiology of preeclampsia. It highlights that the growth, protection, and promotion of the conceptus requires the modulation of an intact maternal immune system, communication between the mother and fetus, and adaptation of the maternal organic functions. A malfunction in any of these factors, on either side, will result in a failure of the cascade of events required for the normal course of pregnancy. Maladaptive processes, initially aiming to protect the conceptus, fail to anticipate the gradually increasing cardiovascular volume load during the course of pregnancy. As a result, multiple organ dysfunctions install progressively and eventually reach a state where mother and/or fetus are at risk of severe morbidity or even mortality, and where the termination of pregnancy becomes the least harmful solution. The helicopter view on pathophysiologic processes associated with preeclampsia, as presented in this paper, illustrates that the etiology of preeclampsia cannot be reduced to one single mechanism, but is to be considered a cascade of consecutive events, fundamentally not unique to pregnancy.

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“…Importantly, Uri‐Belapolsky et al 16 reported that the deletion of the Il1a gene resulted in a higher pregnancy rate in aged mice compared to wild‐type aged mice. Conversely, excessive IL1B causes pregnancy complications, including an increased susceptibility to infectious diseases and inflammation 17–19 . These findings suggest that IL1A and IL1B play crucial roles in the induction of cellular senescence, SASP production, inflammation, aging, and infertility.…”

Section: Introductionmentioning

confidence: 99%

IL1B triggers inflammatory cytokine production in bovine oviduct epithelial cells and induces neutrophil accumulation via CCL2

Nakamura

Aihara

Iwata

et al. 2020

American J Rep Immunol

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Problem The oviduct is essential for reproduction. We previously showed that oviduct epithelial cells (OECs) isolated from aged cows expressed higher levels of inflammatory cytokines, including interleukin (IL) 1A and IL1B. In addition, aging is associated with tissue dysfunction and cellular senescence via a senescence‐associated secretory phenotype (SASP) and immune cell accumulation. We investigated whether IL1A or IL1B causes SASP production, cellular senescence, and inflammatory responses in bovine OECs. Method of Study The OECs were isolated from bovine oviducts from young (mean 50.3 months) and aged cows (mean 157.0 months) and cultured. Results Treatment with IL1A or IL1B induced SASP production (IL8, IL6, TNFA, and CCL2) and mRNA expression of cell adhesion molecules in bovine OECs, but both IL1s did not induce cellular senescence in OECs and migration of polymorphonuclear neutrophils (PMNs). Cultured medium of OECs treated with IL1s, especially IL1B, dramatically induced PMN migration. Treatment with the CCL2 inhibitor, but not IL8 or its receptor CXCR2 inhibitors, significantly reduced immune cell migration in IL1B‐treated OEC‐cultured medium. Treatment with IL1B increased PMN adhesion to OECs, resulting in further SASP production in OECs due to a PMN‐OEC interaction. Conclusion We suggest that senescence‐associated IL1s cause SASP production in bovine OECs and CCL2 induced by IL1B is essential for the migration of immune cells to OECs. Specifically, IL1B regulates PMN migration and adhesion to bovine OECs, and PMNs accelerate inflammatory cytokine production from bovine OECs via a direct interaction. These phenomena may contribute to chronic oviductal inflammation, resulting in subfertility.

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Role of the NLRP3 Inflammasome in Preeclampsia

Cited by 76 publications

References 172 publications

Cholesterol Crystals and NLRP3 Mediated Inflammation in the Uterine Wall Decidua in Normal and Preeclamptic Pregnancies

Cholesterol Crystals and NLRP3 Mediated Inflammation in the Uterine Wall Decidua in Normal and Preeclamptic Pregnancies

Preeclampsia Is a Syndrome with a Cascade of Pathophysiologic Events

IL1B triggers inflammatory cytokine production in bovine oviduct epithelial cells and induces neutrophil accumulation via CCL2

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