The Role of Placental Inflammasomes in Linking the Adverse Effects of Maternal Obesity on Fetal Development

Aye, Irving L.M.H.; Lager, Susanne; Powell, Theresa L.

doi:10.1007/978-3-319-16853-1_6

Cited by 5 publications

(4 citation statements)

References 84 publications

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“…In our study, we report a significant increase in mRNA expression for CASP1 in FGR compared to control pregnancies. These findings are supported by studies that show that CASP1 is detected, and its expression levels increased, in placentae from premature rupture of membrane (PROM) patients [68], women with a high BMI [69], and preeclamptic women [53], all of which are associated with inflammation. Furthermore, Brien et al (2017) report decreased expression of IL-6 and IL-1β following CASP1 inhibition in monosodium urate crystal-induced inflammation in human term placentae [48].…”

Section: Discussionmentioning

confidence: 58%

The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction

Alfian

Chakraborty

Yong

et al. 2022

Cells

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Fetal growth restriction (FGR) is commonly associated with placental insufficiency and inflammation. Nonetheless, the role played by inflammasomes in the pathogenesis of FGR is poorly understood. We hypothesised that placental inflammasomes are differentially expressed and contribute to the aberrant trophoblast function. Inflammasome gene expression profiles were characterised by real-time PCR on human placental tissues collected from third trimester FGR and gestation-matched control pregnancies (n = 25/group). The functional significance of a candidate inflammasome was then investigated using lipopolysaccharide (LPS)-induced models of inflammation in human trophoblast organoids, BeWo cells in vitro, and a murine model of FGR in vivo. Placental mRNA expression of NLRP3, caspases 1, 3, and 8, and interleukin 6 increased (>2-fold), while that of the anti-inflammatory cytokine, IL-10, decreased (<2-fold) in FGR compared with control pregnancies. LPS treatment increased NLRP3 and caspase-1 expression (>2-fold) in trophoblast organoids and BeWo cell cultures in vitro, and in the spongiotrophoblast and labyrinth in the murine model of FGR. However, the LPS-induced rise in NLRP3 was attenuated by its siRNA-induced down-regulation in BeWo cell cultures, which correlated with reduced activity of the apoptotic markers, caspase-3 and 8, compared to the control siRNA-treated cells. Our findings support the role of the NLRP3 inflammasome in the inflammation-induced aberrant trophoblast function, which may contribute to FGR.

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Section: Discussionmentioning

confidence: 58%

The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction

Alfian

Chakraborty

Yong

et al. 2022

Cells

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“…At the molecular level, placentae from obese women were demonstrated to have increased expression of the nucleotide-binding oligomerization domain, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasome, a key mediator of sterile inflammation ( 22 ). Inflammasomes are multiprotein complexes, assembly of which is triggered by both microbial and endogenous danger signals and results in activation and cleavage of caspase-1.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D Supplementation Improves Mitochondrial Function and Reduces Inflammation in Placentae of Obese Women

et al. 2022

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BackgroundAbout 30% of women entering pregnancy in the US are obese. We have previously reported mitochondrial dysregulation and increased inflammation in the placentae of obese women. Vitamin D (VitD) is a major player in calcium uptake and was shown to modulate mitochondrial respiration and the immune/inflammation system. Studies show decreased VitD levels in obese individuals; however, the effect of maternal obesity on VitD metabolism and its association with placental function remains understudied.MethodsMaternal and cord blood plasma and placental samples were collected upon C-section from normal-weight (NW, body mass index [BMI]<25) and obese (OB, BMI>30) women with uncomplicated pregnancies at term. We measured 25(OH)D3 (calcidiol) levels in maternal and cord blood plasma using ELISA. We assessed the expression of CYP27B1, an activator of calcidiol, and Vitamin D receptor (VDR) in placentae from NW and OB, and women with gestational diabetes and preeclampsia. In addition, we examined the effects of VitD supplementation on mitochondrial function and inflammation in trophoblasts from NW and OB, using the Seahorse Bioanalyzer and Western blot, respectively.ResultsVitamin D levels in blood from OB but not NW women and in cord blood from babies born to NW and OB women showed a significant inverse correlation with maternal pre-pregnancy BMI (r=-0.50, p<0.1 and r=-0.55, p=0.004 respectively). Cord plasma VitD levels showed a positive correlation with placental efficiency, i.e., the ratio between fetal and placental weight, as well as with maternal blood VitD levels (r=0.69 and 0.83 respectively, p<0.00). While we found no changes in CYP27B1 in OB vs. NW women, VDR expression were decreased by 50% (p<0.03) independent of fetal sex. No changes in VDR expression relative to BMI-matched controls were observed in the placentae of women with gestational diabetes or preeclampsia. Cytotrophoblasts isolated from placentae of OB women showed a dose-dependent increase in VDR expression after 24-hour treatment with calcitriol (10 nM and 100 nM), an active form of VitD. Trophoblasts isolated from OB women and treated with calcitriol improved mitochondrial respiration (p<0.05). We also found a two-fold increase in expression of the NLRP3 inflammasome and the pro-inflammatory cytokine IL-18 in trophoblasts isolated from placentae of OB women (p<0.05), with IL-18 expression being reversed by calcitriol treatment (100 nM).ConclusionsWe show that VitD deficiency is at least partially responsible for mitochondrial dysfunction and increased inflammation in the placentae of obese women. Vitamin D supplementation could be beneficial in improving placental dysfunction seen in obese women.

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“…How metabolic stressors such as obesity and/or diabetes (or both) modulate gene expression in the placenta remains to be defined. It has been suggested that circulating, saturated free fatty acids (FFAs), such as the ω−6 FFA palmitate, can provoke inflammatory responses in placental cells such as trophoblasts by activating the NLRP3 inflammasome [16,17]. This might be relevant because palmitate levels are elevated in the systemic circulation of pregnant women with prepregnancy obesity [18] and GDM [19].…”

Section: Introductionmentioning

confidence: 99%

Palmitate induces apoptotic cell death and inflammasome activation in human placental macrophages

et al. 2020

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Introduction:There is an increasing prevalence of non-communicable diseases worldwide. Metabolic diseases such as obesity and gestational diabetes mellitus (GDM) increasingly affect women during pregnancy, which can harm pregnancy outcomes and the long-term health and wellbeing of exposed offspring. Both obesity and GDM have been associated with proinflammatory effects within the placenta, the critical organ governing fetal development. Methods:The purpose of these studies was to model, in vitro, the effects of metabolic stress (high levels of glucose, insulin and saturated lipids) on placental macrophage biology, since these cells are the primary innate immune phagocyte within the placenta with roles in governing maternofetal immune tolerance and antimicrobial host defense. Macrophages were isolated from the villous core of term, human placentae delivered through nonlaboring, elective Cesarean #

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The Role of Placental Inflammasomes in Linking the Adverse Effects of Maternal Obesity on Fetal Development

Cited by 5 publications

References 84 publications

The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction

The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction

Vitamin D Supplementation Improves Mitochondrial Function and Reduces Inflammation in Placentae of Obese Women

Palmitate induces apoptotic cell death and inflammasome activation in human placental macrophages

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