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Open AccessArticle

Role of IL-36 Cytokines in the Regulation of Angiogenesis Potential of Trophoblast Cells

by José M. Murrieta-Coxca, Ruby N. Gutiérrez-Samudio, Heba M. El-Shorafa, Tanja Groten, Sandra Rodríguez-Martínez, Mario E. Cancino-Diaz, Juan C. Cancino-Diaz, Rodolfo R. Favaro, Udo R. Markert and Diana M. Morales-Prieto

Int. J. Mol. Sci. 2021, 22(1), 285; https://doi.org/10.3390/ijms22010285 - 30 Dec 2020

Cited by 10 | Viewed by 3324

Abstract

IL-36 cytokines (the agonists IL-36α, IL-36β, IL-36γ, and the antagonist IL-36Ra) are expressed in the mouse uterus and associated with maternal immune response during pregnancy. Here, we characterize the expression of IL-36 members in human primary trophoblast cells (PTC) and trophoblastic cell lines [...] Read more.

IL-36 cytokines (the agonists IL-36α, IL-36β, IL-36γ, and the antagonist IL-36Ra) are expressed in the mouse uterus and associated with maternal immune response during pregnancy. Here, we characterize the expression of IL-36 members in human primary trophoblast cells (PTC) and trophoblastic cell lines (HTR-8/SVneo and JEG-3) and upon treatment with bacterial and viral components. Effects of recombinant IL-36 on the migration capacity of trophoblastic cells, their ability to interact with endothelial cells and the induction of angiogenic factors and miRNAs (angiomiRNAs) were examined. Constitutive protein expression of IL-36 (α, β, and γ) and their receptor (IL-36R) was found in all cell types. In PTC, transcripts for all IL-36 subtypes were found, whereas in trophoblastic cell lines only for IL36G and IL36RN. A synthetic analog of double-stranded RNA (poly I:C) and lipopolysaccharide (LPS) induced the expression of IL-36 members in a cell-specific and time-dependent manner. In HTR-8/SVneo cells, IL-36 cytokines increased cell migration and their capacity to interact with endothelial cells. VEGFA and PGF mRNA and protein, as well as the angiomiRNAs miR-146a-3p and miR-141-5p were upregulated as IL-36 response in PTC and HTR-8/SVneo cells. In conclusion, IL-36 cytokines are modulated by microbial components and regulate trophoblast migration and interaction with endothelial cells. Therefore, a fundamental role of these cytokines in the placentation process and in response to infections may be expected. Full article

(This article belongs to the Special Issue Molecular Aspects of Inflammation in Pregnancy)

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13 pages, 2154 KiB

Open AccessCommunication

Sphingolipid Signature of Human Feto-Placental Vasculature in Preeclampsia

by Ilaria Del Gaudio, Linda Sasset, Annarita Di Lorenzo and Christian Wadsack

Int. J. Mol. Sci. 2020, 21(3), 1019; https://doi.org/10.3390/ijms21031019 - 4 Feb 2020

Cited by 34 | Viewed by 4135

Abstract

Bioactive sphingolipids are emerging as key regulators of vascular function and homeostasis. While most of the clinical studies have been devoted to profile circulating sphingolipids in maternal plasma, little is known about the role of the sphingolipid at the feto-placental vasculature, which is [...] Read more.

Bioactive sphingolipids are emerging as key regulators of vascular function and homeostasis. While most of the clinical studies have been devoted to profile circulating sphingolipids in maternal plasma, little is known about the role of the sphingolipid at the feto-placental vasculature, which is in direct contact with the offspring circulation. Our study aims to compare the sphingolipid profile of normal with preeclamptic (PE) placental chorionic arteries and isolated endothelial cells, with the goal of unveiling potential underlying pathomechanisms in the vasculature. Dihydrosphingosine and sphingomyelin (SM) concentrations (C16:0-, C18:0-, and C24:0- sphingomyelin) were significantly increased in chorionic arteries of preeclamptic placentas, whereas total ceramide, although showing a downward trend, were not statistically different. Moreover, RNA and immunofluorescence analysis showed impaired sphingosine-1-phosphate (S1P) synthesis and signaling in PE vessels. Our data reveal that the exposure to a deranged maternal intrauterine environment during PE alters the sphingolipid signature and gene expression on the fetal side of the placental vasculature. This pathological remodeling consists in increased serine palmitoyltransferase (SPT) activity and SM accrual in PE chorionic arteries, with concomitance impairment endothelial S1P signaling in the endothelium of these vessels. The increase of endothelial S1P phosphatase, lyase and S1PR2, and blunted S1PR1 expression support the onset of the pathological phenotype in chorionic arteries. Full article

(This article belongs to the Special Issue Molecular Aspects of Inflammation in Pregnancy)

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13 pages, 1957 KiB

Open AccessArticle

Maternal Overweight Downregulates MME (Neprilysin) in Feto-Placental Endothelial Cells and in Cord Blood

by Elisa Weiß, Hannah M. Berger, Waltraud T. Brandl, Jasmin Strutz, Birgit Hirschmugl, Violeta Simovic, Carmen Tam-Ammersdorfer, Silvija Cvitic and Ursula Hiden

Int. J. Mol. Sci. 2020, 21(3), 834; https://doi.org/10.3390/ijms21030834 - 28 Jan 2020

Cited by 11 | Viewed by 3127

Abstract

Maternal overweight in pregnancy alters the metabolic environment and generates chronic low-grade inflammation. This affects fetal development and programs the offspring’s health for developing cardiovascular and metabolic disease later in life. MME (membrane-metalloendopeptidase, neprilysin) cleaves various peptides regulating vascular tone. Endothelial cells express [...] Read more.

Maternal overweight in pregnancy alters the metabolic environment and generates chronic low-grade inflammation. This affects fetal development and programs the offspring’s health for developing cardiovascular and metabolic disease later in life. MME (membrane-metalloendopeptidase, neprilysin) cleaves various peptides regulating vascular tone. Endothelial cells express membrane-bound and soluble MME. In adults, the metabolic environment of overweight and obesity upregulates endothelial and circulating MME. We here hypothesized that maternal overweight increases MME in the feto-placental endothelium. We used primary feto-placental endothelial cells (fpEC) isolated from placentas after normal vs. overweight pregnancies and determined MME mRNA, protein, and release. Additionally, soluble cord blood MME was analyzed. The effect of oxygen and tumor necrosis factor α (TNFα) on MME protein in fpEC was investigated in vitro. Maternal overweight reduced MME mRNA (−39.9%, p < 0.05), protein (−42.5%, p = 0.02), and MME release from fpEC (−64.7%, p = 0.02). Both cellular and released MME protein negatively correlated with maternal pre-pregnancy BMI. Similarly, cord blood MME was negatively associated with pre-pregnancy BMI (r = −0.42, p = 0.02). However, hypoxia and TNFα, potential negative regulators of MME expression, did not affect MME protein. Reduction of MME protein in fpEC and in cord blood may alter the balance of vasoactive peptides. Our study highlights the fetal susceptibility to maternal metabolism and inflammatory state. Full article

(This article belongs to the Special Issue Molecular Aspects of Inflammation in Pregnancy)

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11 pages, 1079 KiB

Open AccessCommunication

Neonatal HDL Counteracts Placental Vascular Inflammation via S1P–S1PR1 Axis

by Ilaria Del Gaudio, Sebastian Hendrix, Christina Christoffersen and Christian Wadsack

Int. J. Mol. Sci. 2020, 21(3), 789; https://doi.org/10.3390/ijms21030789 - 25 Jan 2020

Cited by 12 | Viewed by 2974

Abstract

Placental inflammation and dysfunction during pregnancy are associated with short- and long-term adverse outcomes for the offspring. However, the mechanisms of vascular protection at the feto-placental interface are still poorly investigated. The high-density lipoprotein (HDL) associated sphingosine-1-phosphate (S1P) has been described as a [...] Read more.

Placental inflammation and dysfunction during pregnancy are associated with short- and long-term adverse outcomes for the offspring. However, the mechanisms of vascular protection at the feto-placental interface are still poorly investigated. The high-density lipoprotein (HDL) associated sphingosine-1-phosphate (S1P) has been described as a powerful anti-inflammatory complex. This study aimed to elucidate the role of cord blood-derived HDL (nHDL) in feto-placental endothelial dysfunction. Here, we report that the exposure of primary fetal placental arterial endothelial cell (fPAEC) to healthy nHDL-S1P attenuated the ability of TNFα to activate NF-κB signaling and increase the expression of pro-inflammatory markers. Moreover, the angiotensin II (AngII)-induced reactive oxygen species (ROS) production was blunted in the presence of nHDL, whereas it was preserved when the cells were preincubated with S1P receptor antagonists, suggesting that S1P accounts for the vascular protective function of nHDL at the feto-placental unit. These results highlight the importance of HDL and S1P metabolism and signaling in pregnancy pathophysiology. Full article

(This article belongs to the Special Issue Molecular Aspects of Inflammation in Pregnancy)

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14 pages, 3107 KiB

Open AccessArticle

Placental Hofbauer Cell Polarization Resists Inflammatory Cues In Vitro

by Carolin Schliefsteiner, Sandra Ibesich and Christian Wadsack

Int. J. Mol. Sci. 2020, 21(3), 736; https://doi.org/10.3390/ijms21030736 - 22 Jan 2020

Cited by 40 | Viewed by 5671

Abstract

Feto-placental Hofbauer cells (HBCs) are macrophages residing in placental stroma. They are generally described as anti-inflammatory M2 polarized cells, promoting tolerance and tissue remodeling. In certain pathologies, however, a possible phenotypical switch towards pro-inflammatory M1 macrophages has been proposed. The study aimed to [...] Read more.

Feto-placental Hofbauer cells (HBCs) are macrophages residing in placental stroma. They are generally described as anti-inflammatory M2 polarized cells, promoting tolerance and tissue remodeling. In certain pathologies, however, a possible phenotypical switch towards pro-inflammatory M1 macrophages has been proposed. The study aimed to determine if HBCs can acquire an M1 phenotype under pro-inflammatory conditions in vitro. HBCs were isolated from healthy human term placentas. Cells were cultivated upon addition of LPS and INF-γ or IL-4 and IL-13 to induce the M1 and M2 phenotype, respectively. Specific cell polarization markers and cytokines, associated with respective phenotypes, were investigated by flow cytometry and ELISA. THP-1 macrophages served as positive control. Pro-inflammatory stimuli reduced M2 markers CD163 and DC-SIGN, but did not induce M1 markers. TNF-α release was increased, but at the same time TGF-β and IL-10 release was upregulated, resembling in part the M2b sub-phenotype. Anti-inflammatory stimuli had no effect on HBC polarization. HBCs maintain their M2 phenotype in vitro despite inflammatory stimuli, which might represent a state of adaption and tolerance to avoid rejection of the semiallogeneic feto-placental unit. Full article

(This article belongs to the Special Issue Molecular Aspects of Inflammation in Pregnancy)

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18 pages, 5972 KiB

Open AccessArticle

Maternal Obesity Alters Placental Cell Cycle Regulators in the First Trimester of Human Pregnancy: New Insights for BRCA1

by Denise Hoch, Martina Bachbauer, Caroline Pöchlauer, Francisco Algaba-Chueca, Veronika Tandl, Boris Novakovic, Ana Megia, Martin Gauster, Richard Saffery, Andreas Glasner, Gernot Desoye and Alejandro Majali-Martinez

Int. J. Mol. Sci. 2020, 21(2), 468; https://doi.org/10.3390/ijms21020468 - 11 Jan 2020

Cited by 15 | Viewed by 3624

Abstract

In the first trimester of pregnancy, placental development involves a wide range of cellular processes. These include trophoblast proliferation, fusion, and differentiation, which are dependent on tight cell cycle control. The intrauterine environment affects placental development, which also includes the trophoblast cell cycle. [...] Read more.

In the first trimester of pregnancy, placental development involves a wide range of cellular processes. These include trophoblast proliferation, fusion, and differentiation, which are dependent on tight cell cycle control. The intrauterine environment affects placental development, which also includes the trophoblast cell cycle. In this work, we focus on maternal obesity to assess whether an altered intrauterine milieu modulates expression and protein levels of placental cell cycle regulators in early human pregnancy. For this purpose, we use first trimester placental tissue from lean and obese women (gestational week 5⁺⁰–11⁺⁶, n = 58). Using a PCR panel, a cell cycle protein array, and STRING database analysis, we identify a network of cell cycle regulators increased by maternal obesity in which breast cancer 1 (BRCA1) is a central player. Immunostaining localizes BRCA1 predominantly to the villous and the extravillous cytotrophoblast. Obesity-driven BRCA1 upregulation is not able to be explained by DNA methylation (EPIC array) or by short-term treatment of chorionic villous explants at 2.5% oxygen with tumor necrosis factor α (TNF-α) (50 mg/mL), leptin (100 mg/mL), interleukin 6 (IL-6) (100 mg/mL), or high glucose (25 nM). Oxygen tension rises during the first trimester, but this change in vitro has no effect on BRCA1 (2.5% and 6.5% O₂). We conclude that maternal obesity affects placental cell cycle regulation and speculate this may alter placental development. Full article

(This article belongs to the Special Issue Molecular Aspects of Inflammation in Pregnancy)

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12 pages, 2359 KiB

Open AccessArticle

NLRP7 Is Involved in the Differentiation of the Decidual Macrophages

by Pei-Yin Tsai, Kuan-Ru Chen, Yueh-Chun Li and Pao-Lin Kuo

Int. J. Mol. Sci. 2019, 20(23), 5994; https://doi.org/10.3390/ijms20235994 - 28 Nov 2019

Cited by 17 | Viewed by 3807

Abstract

Macrophage polarization, regulated appropriately, may play important roles in successful pregnancy. In the face of the vital roles of decidua macrophages in pregnancy, it is insufficient to recognize the trigger of macrophage differentiation and polarization. We aimed to explore the link between the [...] Read more.

Macrophage polarization, regulated appropriately, may play important roles in successful pregnancy. In the face of the vital roles of decidua macrophages in pregnancy, it is insufficient to recognize the trigger of macrophage differentiation and polarization. We aimed to explore the link between the NLRP7 gene and macrophage polarization in human deciduas. Here, we enrolled the endometrial tissues from eight pregnant women in the first trimester. We found that NLRP7 was abundant in endometrial tissues and that NLRP7 was expressed in decidual macrophages of the first-trimester pregnancy. NLRP7 was predominately expressed in the decidual M2 macrophages, as compared with the M1 macrophages. Furthermore, our results suggest that NLRP7 is associated with decidual macrophage differentiation. NLRP7 over-expression suppresses the expression of M1 markers and enhances the expression of the M2 markers. Considering that NLRP7 relates to decidualization and macrophage differentiation, we propose that NLRP7 is a primate-specific multitasking gene to maintain endometrial hemostasis and reproductive success. This finding may pave the way for therapies of pathological pregnancies. Full article

(This article belongs to the Special Issue Molecular Aspects of Inflammation in Pregnancy)

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Review

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28 pages, 1490 KiB

Open AccessReview

Maternal Obesity and the Uterine Immune Cell Landscape: The Shaping Role of Inflammation

by Lauren E. St-Germain, Barbara Castellana, Jennet Baltayeva and Alexander G. Beristain

Int. J. Mol. Sci. 2020, 21(11), 3776; https://doi.org/10.3390/ijms21113776 - 27 May 2020

Cited by 36 | Viewed by 5071

Abstract

Inflammation is often equated to the physiological response to injury or infection. Inflammatory responses defined by cytokine storms control cellular mechanisms that can either resolve quickly (i.e., acute inflammation) or remain prolonged and unabated (i.e., chronic inflammation). Perhaps less well-appreciated is the importance [...] Read more.

Inflammation is often equated to the physiological response to injury or infection. Inflammatory responses defined by cytokine storms control cellular mechanisms that can either resolve quickly (i.e., acute inflammation) or remain prolonged and unabated (i.e., chronic inflammation). Perhaps less well-appreciated is the importance of inflammatory processes central to healthy pregnancy, including implantation, early stages of placentation, and parturition. Pregnancy juxtaposed with disease can lead to the perpetuation of aberrant inflammation that likely contributes to or potentiates maternal morbidity and poor fetal outcome. Maternal obesity, a prevalent condition within women of reproductive age, associates with increased risk of developing multiple pregnancy disorders. Importantly, chronic low-grade inflammation is thought to underlie the development of obesity-related obstetric and perinatal complications. While diverse subsets of uterine immune cells play central roles in initiating and maintaining healthy pregnancy, uterine leukocyte dysfunction as a result of maternal obesity may underpin the development of pregnancy disorders. In this review we discuss the current knowledge related to the impact of maternal obesity and obesity-associated inflammation on uterine immune cell function, utero-placental establishment, and pregnancy health. Full article

(This article belongs to the Special Issue Molecular Aspects of Inflammation in Pregnancy)

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13 pages, 1262 KiB

Open AccessReview

The Role of NFκB in Healthy and Preeclamptic Placenta: Trophoblasts in the Spotlight

by Brooke Armistead, Leena Kadam, Sascha Drewlo and Hamid-Reza Kohan-Ghadr

Int. J. Mol. Sci. 2020, 21(5), 1775; https://doi.org/10.3390/ijms21051775 - 5 Mar 2020

Cited by 55 | Viewed by 7480

Abstract

The NFκB protein family regulates numerous pathways within the cell—including inflammation, hypoxia, angiogenesis and oxidative stress—all of which are implicated in placental development. The placenta is a critical organ that develops during pregnancy that primarily functions to supply and transport the nutrients required [...] Read more.

The NFκB protein family regulates numerous pathways within the cell—including inflammation, hypoxia, angiogenesis and oxidative stress—all of which are implicated in placental development. The placenta is a critical organ that develops during pregnancy that primarily functions to supply and transport the nutrients required for fetal growth and development. Abnormal placental development can be observed in numerous disorders during pregnancy, including fetal growth restriction, miscarriage, and preeclampsia (PE). NFκB is highly expressed in the placentas of women with PE, however its contributions to the syndrome are not fully understood. In this review we discuss the molecular actions and related pathways of NFκB in the placenta and highlight areas of research that need attention Full article

(This article belongs to the Special Issue Molecular Aspects of Inflammation in Pregnancy)

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16 pages, 1005 KiB

Open AccessReview

The Role of Macrophages in Oocyte Donation Pregnancy: A Systematic Review

by Xuezi Tian, Michael Eikmans and Marie-Louise van der Hoorn

Int. J. Mol. Sci. 2020, 21(3), 939; https://doi.org/10.3390/ijms21030939 - 31 Jan 2020

Cited by 5 | Viewed by 3042

Abstract

The embryo of an oocyte donation (OD) pregnancy is completely allogeneic to the mother, which leads to a more serious challenge for the maternal immune system to tolerize the fetus. It is thought that macrophages are essential in maintaining a healthy pregnancy, by [...] Read more.

The embryo of an oocyte donation (OD) pregnancy is completely allogeneic to the mother, which leads to a more serious challenge for the maternal immune system to tolerize the fetus. It is thought that macrophages are essential in maintaining a healthy pregnancy, by acting in immunomodulation and spiral arterial remodeling. OD pregnancies represent an interesting model to study complex immunologic interactions between the fetus and the pregnant woman since the embryo is totally allogeneic compared to the mother. Here, we describe a narrative review on the role of macrophages and pregnancy and a systematic review was performed on the role of macrophages in OD pregnancies. Searches were made in different databases and the titles and abstracts were evaluated by three independent authors. In total, four articles were included on OD pregnancies and macrophages. Among these articles, some findings are conflicting between studies, indicating that more research is needed in this area. From current research, we could identify that there are multiple subtypes of macrophages, having diverse biological effects, and that the ratio between subtypes is altered during gestation and in aberrant pregnancy. The study of macrophages’ phenotypes and their functions in OD pregnancies might be beneficial to better understand the maternal-fetal tolerance system. Full article

(This article belongs to the Special Issue Molecular Aspects of Inflammation in Pregnancy)

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19 pages, 1983 KiB

Open AccessReview

Molecular Modelling of Islet β-Cell Adaptation to Inflammation in Pregnancy and Gestational Diabetes Mellitus

by Petra I. Lorenzo, Alejandro Martín-Montalvo, Nadia Cobo Vuilleumier and Benoit R. Gauthier

Int. J. Mol. Sci. 2019, 20(24), 6171; https://doi.org/10.3390/ijms20246171 - 6 Dec 2019

Cited by 27 | Viewed by 5573

Abstract

Gestational diabetes mellitus (GDM), a metabolic disease that develops with the increase in insulin resistance during late pregnancy, is currently one of the most common complications affecting pregnancy. The polygenic nature of GDM, together with the interplay between different genetic variants with nutritional [...] Read more.

Gestational diabetes mellitus (GDM), a metabolic disease that develops with the increase in insulin resistance during late pregnancy, is currently one of the most common complications affecting pregnancy. The polygenic nature of GDM, together with the interplay between different genetic variants with nutritional and environmental factors has hindered the full understanding of the etiology of this disease. However, an important genetic overlap has been found with type 2 diabetes mellitus (T2DM) and, as in the case of T2DM, most of the identified loci are associated with β-cell function. Early detection of GDM and adequate interventions to control the maternal glycemia are necessary to avoid the adverse outcomes for both the mother and the offspring. The in utero exposure to the diabetic milieu predispose these children for future diseases, among them T2DM, originating a vicious circle implicated in the increased prevalence of both GDM and T2DM. The involvement of inflammatory processes in the development of GDM highlights the importance of pancreatic β-cell factors able to favor the adaptation processes required during gestation, concomitantly with the protection of the islets from an inflammatory milieu. In this regard, two members of the Pax family of transcription factors, PAX4 and PAX8, together with the chromatin remodeler factor HMG20A, have gained great relevance due to their involvement in β-cell mass adaptation together with their anti-inflammatory properties. Mutations in these factors have been associated with GDM, highlighting these as novel candidates for genetic screening analysis in the identification of women at risk of developing GDM. Full article

(This article belongs to the Special Issue Molecular Aspects of Inflammation in Pregnancy)

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15 pages, 2036 KiB

Open AccessReview

Maternal Platelets—Friend or Foe of the Human Placenta?

by Gerit Moser, Jacqueline Guettler, Désirée Forstner and Martin Gauster

Int. J. Mol. Sci. 2019, 20(22), 5639; https://doi.org/10.3390/ijms20225639 - 11 Nov 2019

Cited by 34 | Viewed by 6247

Abstract

Human pregnancy relies on hemochorial placentation, including implantation of the blastocyst and deep invasion of fetal trophoblast cells into maternal uterine blood vessels, enabling direct contact of maternal blood with placental villi. Hemochorial placentation requires fast and reliable hemostasis to guarantee survival of [...] Read more.

Human pregnancy relies on hemochorial placentation, including implantation of the blastocyst and deep invasion of fetal trophoblast cells into maternal uterine blood vessels, enabling direct contact of maternal blood with placental villi. Hemochorial placentation requires fast and reliable hemostasis to guarantee survival of the mother, but also for the neonates. During human pregnancy, maternal platelet count decreases gradually from first, to second, and third trimester. In addition to hemodilution, accelerated platelet sequestration and consumption in the placental circulation may contribute to a decline of platelet count throughout gestation. Local stasis, turbulences, or damage of the syncytiotrophoblast layer can activate maternal platelets within the placental intervillous space and result in formation of fibrin-type fibrinoid. Perivillous fibrinoid is a regular constituent of the normal placenta which is considered to be an important regulator of intervillous hemodynamics, as well as having a role in shaping the developing villous trees. However, exaggerated activation of platelets at the maternal-fetal interface can provoke inflammasome activation in the placental trophoblast, and enhance formation of circulating platelet-monocyte aggregates, resulting in sterile inflammation of the placenta and a systemic inflammatory response in the mother. Hence, the degree of activation determines whether maternal platelets are a friend or foe of the human placenta. Exaggerated activation of maternal platelets can either directly cause or propagate the disease process in placenta-associated pregnancy pathologies, such as preeclampsia. Full article

(This article belongs to the Special Issue Molecular Aspects of Inflammation in Pregnancy)

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