Neutrophil extracellular traps are critical for pregnancy loss in sphingosine kinase–deficient mice on 129Sv/C57BL/6 background

Mizugishi, Kiyomi; Yamashita, Kouhei

doi:10.1096/fj.201700399rr

Cited by 20 publications

(9 citation statements)

References 47 publications

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“…In the PAD4 deficient mice, however, overexpression of this same protein resulted in a significantly dampened inflammatory and thrombotic response with a correspondingly lower rate of pregnancy loss. Similarly, Mizugishi and Yamashita demonstrated that NETs also appear to play a role in sphingosine kinase-mediated pregnancy loss [46]. In their murine model, inhibition of the activated sphingolipid metabolic pathway by way of sphingosine kinase gene disruption resulted in increased NET formation specifically at the fetomaternal interface and associated early fetal death.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils

Weeding

Coit

Yalavarthi

et al. 2018

Clinical Immunology

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Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thromboembolic events and pregnancy loss. We sought to characterize the DNA methylation profile of primary APS in comparison to healthy controls and individuals with SLE. In primary APS neutrophils compared to controls, 17 hypomethylated and 25 hypermethylated CpG sites were identified. Notable hypomethylated genes included ETS1, a genetic risk locus for SLE, and PTPN2, a genetic risk locus for other autoimmune diseases. Gene ontology analysis of hypomethylated genes revealed enrichment of genes involved in pregnancy. None of the differentially methylated sites in primary APS were differentially methylated in SLE neutrophils, and there was no demethylation of interferon signature genes in primary APS as is seen in SLE. Hypomethylation within a single probe in the IFI44L promoter (cg06872964) was able to distinguish SLE from primary APS with a sensitivity of 93.3% and specificity of 80.0% at a methylation fraction of 0.329.

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Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils

Weeding

Coit

Yalavarthi

et al. 2018

Clinical Immunology

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“…The pro-NETotic effect of the GDM patients' plasma was attenuated with a TNF-a antagonist (99). As PAD4/NETs are implicated in animal models of pregnancy loss (100,101), the gravity of GDM should not be underestimated (102). Increased spontaneous NETosis in diabetes contributes to diabetic complications.…”

Section: Diabetes and Its Complicationsmentioning

confidence: 99%

Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging

Wong

Wagner

2018

The FASEB Journal

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Peptidylarginine deiminase 4 (PAD4) is a nuclear citrullinating enzyme that is critically involved in the release of decondensed chromatin from neutrophils as neutrophil extracellular traps (NETs). NETs, together with fibrin, are implicated in host defense against pathogens; however, the formation of NETs (NETosis) has injurious effects that may outweigh their protective role. For example, PAD4 activity produces citrullinated neoantigens that promote autoimmune diseases, such as rheumatoid arthritis, to which PAD4 is genetically linked and where NETosis is prominent. NETs are also generated in basic sterile inflammatory responses that are induced by many inflammatory stimuli, including cytokines, hypoxia, and activated platelets. Mice that lack PAD4-deficient in NETosis-serve as an excellent tool with which to study the importance of NETs in disease models. In recent years, animal and human studies have demonstrated that NETs contribute to the etiology and propagation of many common noninfectious diseases, the focus of our review. We will discuss the role of NETs in thrombotic and cardiovascular disease, the induction of NETs by cancers and its implications for cancer progression and cancer-associated thrombosis, and elevated NETosis in diabetes and its negative impact on wound healing, and will propose a link between PAD4/NETs and age-related organ fibrosis. We identify unresolved issues and new research directions.-Wong, S. L., Wagner, D. D. Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging.

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“…This specific modification has been described as a marker of NETosis 27 and Giaglis and collaborators have already shown that NETs increase during gestation and peak at term. 28 Citrullinated H3 is found in decidual cells in mice 29 and is involved in insulinlike growth factor-binding protein 1 (IGFBP1) regulation, which is important for migration and attachment of trophoectoderm to the endometrium. 30 Additionally, H3K27me3, a repressive modification, is also found in decidual cells 31 and its level increased on metalloprotease 2 and 9 (MMP2 and MMP9) promoters in third trimester placental villi compared with first trimester ones.…”

Section: Discussionmentioning

confidence: 99%

NETosis Markers in Pregnancy: Effects Differ According to Histone Subtypes

et al. 2021

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NETosis is an innate immune response occurring after infection or inflammation: activated neutrophils expel decondensed DNA in complex with histones into the extracellular environment in a controlled manner. It activates coagulation and fuels the risk of thrombosis. Human pregnancy is associated with a mild proinflammatory state characterized by circulatory neutrophil activation which is further increased in complicated pregnancies, placenta-mediated complications being associated with an increased thrombotic risk. This aberrant activation leads to an increased release of nucleosomes in the blood flow. The aim of our study was to initially quantify nucleosome-bound histones in normal pregnancy and in placenta-mediated complication counterpart. We analyzed the role of histones on extravillous trophoblast function. Circulating nucleosome-bound histones H3 (Nu.QH3.1, Nu.QH3PanCit, Nu.QH3K27me3) and H4 (Nu.QH4K16Ac) were increased in complicated pregnancies. In vitro using the extravillous cell line HTR-8/SVNeo, we observed that free recombinant H2B, H3, and H4 inhibited migration in wound healing assay, but only H3 also blocked invasion in Matrigel-coated Transwell experiments. H3 and H4 also induced apoptosis, whereas H2B did not. Finally, the negative effects of H3 on invasion and apoptosis could be restored with enoxaparin, a low-molecular-weight heparin (LMWH), but not with aspirin. Different circulating nucleosome-bound histones are increased in complicated pregnancy and this would affect migration, invasion, and induce apoptosis of extravillous trophoblasts. Histones might be part of the link between the risk of thrombosis and pregnancy complications, with an effect of LMWH on both.

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Neutrophil extracellular traps are critical for pregnancy loss in sphingosine kinase–deficient mice on 129Sv/C57BL/6 background

Cited by 20 publications

References 47 publications

Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils

Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils

Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging

NETosis Markers in Pregnancy: Effects Differ According to Histone Subtypes

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