Estrogen-induced NETs promote aseptic inflammation via NKCC1
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PROVIDER: PRJNA927007 | ENA |
REPOSITORIES: ENA
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Project description:Estrogen-induced NETs promote aseptic inflammation via NKCC1 [human]
| PRJNA927014 | ENA
Project description:Although the formation of neutrophil extracellular traps (NETs) is caused by inflammation-related factors, it remains unclear whether endogenous hormones promote NET formation. Here, we investigate NET formation between infection-driven inflammatory endometrium and estrogen-induced hyperplastic endometrium by single-cell multiomics analysis. We identified a unique neutrophil subpopulation (CD24high neutrophil) involved in estrogen-driven NET formation. Estrogen-induced NETs mainly form due to the imbalance of histone caused by estrogen receptors. Inhibition of NETs significantly ameliorated endometrial hyperplasia (EH) in a murine model. Mechanistically, NETs promote cell proliferation by binding to NKCC1 on epithelial cells. Aspirin was screened to inhibit NET formation and alleviated EH in cynomolgus monkey. This study provides a novel nonhormone replacement therapy to treat patients with estrogen abnormalities by targeting NETs.
2025-01-29 | GSE223639 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-01-31 | GSE223643 | GEO
Project description:Neutrophil extracellular traps (NETs) promote inflammation and atherosclerosis progression. In diabetes they are increased and impair wound healing, during which inflammation normally resolves. Atherosclerosis regression, a process resembling wound healing, is also impaired in diabetes. Thus, we hypothesized that NETs impede atherosclerosis regression in diabetes through unresolved inflammation. Objective: To investigate in diabetes the effect of NETs on plaque macrophage inflammation and whether NETs reduction improves atherosclerosis regression. Findings: Transcriptomic profiling of plaque macrophages from NET positive and negative areas in Ldlr-/- mice revealed inflammasome and glycolysis pathway upregulation, indicating a pro-inflammatory phenotype. During atherosclerosis regression in non-diabetic mice, plaque NET content decreased. In contrast, in diabetic mouse plaques NETs were enriched and persisted after lipid-lowering. DNase1 treatment (to degrade NETs) of diabetic mice reduced plaque NETs and macrophage inflammation and improved atherosclerosis regression after lipid-lowering. Conclusions: NETs decline during atherosclerosis regression in non-diabetic mice, but persist in diabetes and impair regression by exacerbating macrophage inflammation. DNase1 reduced diabetic plaque NETs and macrophage inflammation, and restored atherosclerosis resolution after lipid-lowering, despite ongoing hyperglycemia. Given that humans with diabetes also exhibit impaired atherosclerosis resolution with lipid-lowering, these data suggest that NETs contribute to the increased CVD risk in this population.
2020-05-12 | GSE145200 | GEO
Project description:Increasing evidence has demonstrated that circular RNA exerts important function in the pathogenesis of some diseases. While, the contributions of circRNAs to aseptic lossening after total hip arthroplasty remain largely unknown. Our research is to explore the differently expressed circRNAs and elucidate complex regulated mechanism of circRNAs in aseptic lossening. The differently expressed circRNAs were identified by RNA sequencing analysis. Reverse transcription-quantitative polymerase chain reaction was adopted to corroborate these differently expressed circRNAs. The potential function of circRNAs in aseptic lossening tissue was identified by competing endogenous RNA analysis. Enrichment analysis were performed for target mRNAs and host genes of the differently expressed circRNAs by Gene Oncology and Kyoto Encyclopedia of Genes and Genomes. 257 differently expressed circRNAs were obtained from RNA-seq results. Then, circRNA–miRNA–mRNA network was established based on the validated circRNAs. The result of Gene Oncology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggested that the circRNAs were related with some biological functions and pathways of aseptic lossening. A novel pathogenesis and treatment strategy about aseptic lossening after total hip arthroplasty was revealed from our study of circRNA–miRNA–mRNA network.
2021-01-19 | GSE149315 | GEO
Project description:Aseptic loosening represents a significant factor contributing to joint replacement failure, primarily associated with diminished bone formation and heightened osteoclast-induced osteolysis. Here, a natural polymer-based injectable hydrogel that encapsulates irisin protein (referred to as I-OG hydrogel) is reported. The hierarchical cross-linked structure of the I-OG hydrogel confers favorable mechanical properties, desirable self-healing ability, and acceptable injectability and, more importantly, sustains continuous release of the protein at the interface between the bone and implant prosthesis. The I-OG hydrogel effectively fills the gap between the titanium pin and bone tissue, successfully inhibiting aseptic loosening induced by titanium particles, which outcome confirms the occurrence of irisin protein's slow-release process and its inhibitory effect on osteolysis. Mechanistically, our in vitro experiments demonstrated that irisin released from the I-OG hydrogel upregulates the Wnt/β-catenin signaling pathway in bone marrow stromal cells (BMSCs) through integrin αV, while concurrently downregulating the NF-κB (P65) signaling pathway in osteoblasts. These molecular events ultimately promote osteogenic differentiation and inhibit osteoclast activation. Collectively, our findings establish that the I-OG hydrogel effectively counteracts aseptic loosening by resisting osteolysis caused by titanium particles and enhancing periprosthetic bone formation, and offers promising prospects for the treatment of aseptic loosening in prosthetic implants.
2023-06-17 | GSE234863 | GEO
Project description:Neutrophil Extracellular Traps (NETs) promote macrophage inflammation and impair atherosclerosis resolution in mice with diabetes
| PRJNA606287 | ENA
Project description:The occurrence of cardiovascular diseases increases dramatically in postmenopausal aged women. Accumulating evidence has indicated that estrogen protects hearts from cardiovascular diseases. However, the underlying mechanisms was not fully elucidated. This present study was designed to investigate the function of GPR30 in pathological heart failure of aged female mice with the focus of neutrophil extracellular traps (NETs). Transverse aortic constriction (TAC) surgery was performed to induce heart failure in aged female mice. RNA-seq and flow cytometry were employed to study neutrophils activity during heart failure of aged female mice. Heart function and cardiac fibrosis as well as NETs level were assessed. Reduction of NETs by DNase I administration、 G1 treatment and Trex1 overexpression in macrophage were conducted to elucidate the role of NETs in this pathological process. Co-culture of RAW264.7 macrophages and neutrophils were used to examine the function of Trex1 in macrophage. Our bulk RNA-seq analysis showed that neutrophil migration and neutrophil chemotaxis were markedly enhanced at the early stage of pathological cardiac hypertrophy in aged female hearts. We further demonstrated that NETs generated by these activated neutrophils in aged female myocardium at the late stage were significantly increased following TAC surgery accompanied with the reduction of GPR30 expression. GPR30 agonist G1 treatment preserved cardiac function and reduced myocardial fibrosis in aged female mice with heart failure. To further validate the key role of NETs, DNase I administration markedly enhanced cardiac performance and attenuated cardiac fibrosis with the overall neutrophil reduction in the myocardium. Our in vitro results showed that overexpression of Trex1 in RAW264.1 macrophage enhanced neutrophil NETs clearance, thus indicating that GPR30 activation could increase the exonuclease three prime repair exonuclease 1 (Trex1) expression which may be associated with the reduction of NETs level in hypertrophied hearts. NETs generated by neutrophils exacerbate pressure overload–induced heart failure in aged female mice. GPR30 activates Trex1 signaling in macrophage to enhance NTEs degradation and thus attenuates TAC-induced cardiac dysfunction, providing an avenue for the novel therapeutics against cardiac dysfunction in postmenopausal women.
2026-03-31 | GSE322841 | GEO
Project description:Background: Osteoporosis and diabetes represent major global public health challenges. Neutrophil extracellular traps (NETs) serve as key components of the innate immune system by capturing bacteria, fungi, and parasites, thereby trapping them in local environments with high concentrations of antimicrobial agents leading to their elimination. This study aimed to identify biomarkers associated with NETs in osteoporosis with diabetes, and to explore the underlying molecular mechanisms. Methods: A transcriptomic sequencing dataset was obtained for osteoporosis combined with diabetes. The NETs-related genes (NETs-RGs) were obtained from previous literature. Biomarkers were identified through differential analysis, machine learning, and receiver operating characteristic (ROC). The identified biomarkers were further validated by qRT-PCR and ELISA. Subsequently, molecular regulatory network construction, immune infiltration analysis, enrichment analysis, and drug prediction were conducted. Results: S100A12 and SLC25A37 were identified as biomarkers. Their significant upregulation at the protein level was further confirmed by experimental validation in an independent cohort. Enrichment analysis indicated that S100A12 was significantly enriched in 68 pathways, including \"ECM receptor interaction\", \"maturity onset diabetes of the young\", and others. SLC25A37 was significantly enriched in 54 pathways, primarily including \"ribosome\", \"leishmania infection\", and \"Toll-like receptor signaling pathway\". A total of 7 immune cell types exhibited significant differences between the two groups, including neutrophils and regulatory T cells. A total of 59 miRNAs and 43 lncRNAs were predicted. Additionally, XIST-hsa-miR-146a-5p-S100A12 and XIST-hsa-miR-7-5-SLC25A37 were suggested to have potential regulatory roles in osteoporosis with diabetes. Drugs such as rimegepant and eptinezumab were associated with biomarkers. Conclusion: S100A12 and SLC25A37 were identified as biomarkers associated with NETs in osteoporosis with diabetes, providing a theoretical foundation for developing targeted treatments for osteoporosis with diabetes.
2026-01-11 | E-MTAB-16559 | biostudies-arrayexpress
Project description:Background Adenosine Deaminase 2 Deficiency (DADA2) is an autoinflammatory disease characterized by systemic vasculopathy, strokes and mild immunodeficiency. Recently NETosis has been implicated in the pathogenesis of Deficiency of Adenosine Deaminase 2. Objectives To deep investigate the possible effects of NETs on the immune system we characterized proteomic profile of NETs from DADA2 as compared to HD and Polyarteritis Nodosa (PAN) patients. To determine if NETs contain possibly immunogenic antigens we study functional aspects on Dendritic Cells after in vitro stimulation with NETs. Methods Twenty two DADA2 patients were enrolled. We analyzed NETosis by Imaging Flow Citometry. We evaluated NETs remnants and DNAse in the plasma samples by ELISA assay whereas DNAse activity by DNA digestion. We used quantitative proteomics approach to identify NET proteins in 6 DADA2, 7 PAN and 7 HD. Results Neutrophils from DADA2 patients show a significant increased suicidal NETosis. DNAse enzymes were not normal in the level or activity. By proteomic analysis we identified 1356 proteins among which a hundred of proteins were significantly up or down-modulated in DADA2 NETs as compared to controls NETs in resting condition and after stimulation with PMA, Adenosine and TNFα. DADA2 NETs are significantly more efficient than normal NETs in stimulating patients’ monocyte-derived dendritic cells. Conclusion We identified different pathways significantly upregulated or downregulated in DADA2 NETs versus PAN/HD NETs. This peculiar protein profile could be contribute to activate inflammatory pathways in Dendritic cells in DADA2.
2025-06-23 | PXD055246 | Pride