Human Macrophage Long Intergenic Non-coding RNA, SIMALR, Suppresses Inflammatory Macrophage Apoptosis via Netrin 1
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ABSTRACT:
PROVIDER: PRJNA875269 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21373964_1.fastq.gz | Fastqsanger.gz | |||
| SRR21373964_2.fastq.gz | Fastqsanger.gz | |||
| SRR21373965_1.fastq.gz | Fastqsanger.gz | |||
| SRR21373965_2.fastq.gz | Fastqsanger.gz | |||
| SRR21373966_1.fastq.gz | Fastqsanger.gz |
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Project description:Long noncoding RNAs (lncRNAs) have emerged as novel regulators of macrophage biology and related inflammatory cardiovascular diseases. However, studies focused on lncRNAs in human macrophage subtypes, particularly human lncRNAs that are not conserved in rodents, are limited. Through RNA-seq of human monocyte-derived macrophages, we identified Suppressor of Inflammatory Macrophage Apoptosis lncRNA (SIMALR), a human macrophage-specific long intergenic noncoding RNA, to be highly induced in LPS/IFNγ-stimulated macrophages. Treatment of LPS/IFNγ stimulated THP1 human macrophages with SIMALR antisense oligonucleotides induced apoptosis of inflammatory macrophages, as shown by increased protein expression of cleaved PARP, caspase 9, caspase 3, and Annexin V+. RNA-seq of control versus SIMALR knockdown in LPS/IFNγ-stimulated human monocyte derived macrophages showed NTN1 to be significantly decreased upon SIMALR knockdown. As expected, NTN1 knockdown in LPS/IFNγ-stimulated macrophages induced apoptosis. This apoptotic phenotype was attenuated by adding recombinant NTN1 after SIMALR knockdown. Furthermore, NTN1 promoter-luciferase reporter activity was increased in HEK293T cells treated with lentiviral overexpression of SIMALR. NTN1 promoter activity is known to require HIF1α. RNA immunoprecipitation and microscopy studies suggest that SIMALR may interact with HIF1α to regulate NTN1 transcription, thereby regulating apoptosis of macrophages. In translational studies, SIMALR was found to be expressed in macrophages in human carotid atherosclerotic plaques of symptomatic patients. SIMALR is a non-conserved, human macrophage lincRNA expressed in human atherosclerosis that regulates macrophage apoptosis. SIMALR partners with HIF1α to regulate NTN1, which is a known macrophage survival factor. This work illustrates the importance of interrogating the functions of non-conserved human lincRNAs and exploring their translational and therapeutic potential in human atherosclerosis.
2022-11-23 | GSE212381 | GEO
Project description:BackgroundLong noncoding RNAs (lncRNAs) have emerged as novel regulators of macrophage biology and inflammatory cardiovascular diseases. However, studies focused on lncRNAs in human macrophage subtypes, particularly human lncRNAs that are not conserved in rodents, are limited.MethodsThrough RNA-sequencing of human monocyte-derived macrophages, we identified suppressor of inflammatory macrophage apoptosis lncRNA (SIMALR). Lipopolysaccharide/IFNγ (interferon γ) stimulated human macrophages were treated with SIMALR antisense oligonucleotides and subjected to RNA-sequencing to investigate the function of SIMALR. Western blots, luciferase assay, and RNA immunoprecipitation were performed to validate function and potential mechanism of SIMALR. RNAscope was performed to identify SIMALR expression in human carotid atherosclerotic plaques.ResultsRNA-sequencing of human monocyte-derived macrophages identified SIMALR, a human macrophage-specific long intergenic noncoding RNA that is highly induced in lipopolysaccharide/IFNγ-stimulated macrophages. SIMALR knockdown in lipopolysaccharide/IFNγ stimulated THP1 human macrophages induced apoptosis of inflammatory macrophages, as shown by increased protein expression of cleaved PARP (poly[ADP-ribose] polymerase), caspase 9, caspase 3, and Annexin V+. RNA-sequencing of control versus SIMALR knockdown in lipopolysaccharide/IFNγ-stimulated macrophages showed Netrin-1 (NTN1) to be significantly decreased upon SIMALR knockdown. We confirmed that NTN1 knockdown in lipopolysaccharide/IFNγ-stimulated macrophages induced apoptosis. The SIMALR knockdown-induced apoptotic phenotype was rescued by adding recombinant NTN1. NTN1 promoter-luciferase reporter activity was increased in HEK293T (human embryonic kidney 293) cells treated with lentiviral overexpression of SIMALR. NTN1 promoter activity is known to require HIF1α (hypoxia-inducible factor 1 subunit alpha), and our studies suggest that SIMALR may interact with HIF1α to regulate NTN1 transcription, thereby regulating macrophages apoptosis. SIMALR was found to be expressed in macrophages in human carotid atherosclerotic plaques of symptomatic patients.ConclusionsSIMALR is a nonconserved, human macrophage lncRNA expressed in atherosclerosis that suppresses macrophage apoptosis. SIMALR partners with HIF1α (hypoxia-inducible factor 1 subunit alpha) to regulate NTN1, which is a known macrophage survival factor. This work illustrates the importance of interrogating the functions of human lncRNAs and exploring their translational and therapeutic potential in human atherosclerosis.
| S-EPMC10162399 | biostudies-literature
Project description:OGT suppresses macrophage proinflammatory activation
| PRJNA607991 | ENA
Project description:The generation of induced pluripotent stem (iPS) cells holds great promise in regenerative medicine. However, the relative flaws in the understanding of the molecular mechanisms promoting or limiting reprogramming still hinder the efficient generation of high quality iPS cells. Whereas modulation of the initial Oct4, Sox2, Klf4 and c-Myc (OSKM) cocktail with new transcription factors has been extensively documented, comparatively little is known about soluble molecules promoting the process, even if such recombinant factors could be highly valuable for therapeutic applications. In this study we developed a large-scale identification method to uncover novel programmed cell death (PCD)-related mechanisms limiting somatic cell reprogramming to pluripotency (SCRP). We identified Netrin-1 and its dependence receptor Dcc (Deleted in Colorectal Carcinoma), previously described for their respective survival/death functions both in normal and oncogenic contexts, as novel key SCRP modulators. We show that the early phase of SCRP is accompanied with a strong Netrin-1 deficiency, due to the improper epigenetic regulation of the Ntn1 promoter by OSKM. Mechanistically, we demonstrate that such Netrin-1 imbalance induces apoptosis mediated by the dependence receptor Dcc in a p53-independent manner. Correction of the Netrin-1/Dcc equilibrium by gain-of-ligand and loss-of-receptor experiments constrains apoptosis and improves reprogramming. As a consequence, we propose a novel iPS derivation protocol including a sequential treatment with recombinant Netrin1 that greatly facilitates the generation of mouse and human iPS cells. RNA-sequencing of mouse embryonic fibroblasts (passage 2 and passage 4), mouse pre-iPS cells (passage 5 and passage 25), 1 clone of control iPS (passage 5 and passage 25) and 2 independent clones of "Netrin-1 derived" iPS cells (passage 5 and passage 25). For this analysis, mouse iPS cell lines were grown in KSR+LIF media.
2015-09-01 | E-GEOD-54107 | biostudies-arrayexpress
Project description:Floor plate-derived extracellular signaling molecules, including canonical axon guidance cues of the Netrin family, control neuronal circuit organization. Despite the importance of the floor plate as an essential signaling centre in the developing vertebrate central nervous system, no systematic approach to identify binding partners for floor plate-expressed cellsurface and secreted proteins has been carried out. Here, we used a high-throughput assay to discover extracellular protein-protein interactions, which likely take place in the zebrafish floor plate microenvironment. The assembled floor plate network contains 47 interactions including the hitherto not reported interaction between Netrin-1 and Draxin. We further characterized this interaction, narrowed down the binding interface, and demonstrated that Draxin competes with Netrin receptors for binding to Netrin-1. Our results suggest that Draxin functions as an extracellular Netrin signaling modulator in vertebrates. A reciprocal gradient of Draxin might shape or sharpen the active Netrin gradient, thereby critically modulating its effect.
2015-05-31 | E-MTAB-3609 | biostudies-arrayexpress
Project description:Overnutrition leads to metabolic disorders such as obesity and diabetes. Enhanced inflammation has also been shown to be an essential player in the progression of metabolic diseases. However, how immune cells sense nutritional status and contribute to whole-body metabolism remain largely elusive. OGT-catalyzed protein O-GlcNAcylation is thought to be a metabolic sensor that modulates cell signaling. In this study, we show that overnutrition stimulates macrophage O-GlcNAc signaling. O-GlcNAc signaling suppresses macrophage proinflammatory activation and protects against diet-induced obesity and metabolic dysfunction. These findings thus identify macrophage O-GlcNAc signaling as a novel homeostatic regulator at the interface of inflammation and metabolism.
2020-07-22 | GSE145720 | GEO
Project description:The generation of induced pluripotent stem (iPS) cells holds great promise in regenerative medicine. However, the relative flaws in the understanding of the molecular mechanisms promoting or limiting reprogramming still hinder the efficient generation of high quality iPS cells. Whereas modulation of the initial Oct4, Sox2, Klf4 and c-Myc (OSKM) cocktail with new transcription factors has been extensively documented, comparatively little is known about soluble molecules promoting the process, even if such recombinant factors could be highly valuable for therapeutic applications. In this study we developed a large-scale identification method to uncover novel programmed cell death (PCD)-related mechanisms limiting somatic cell reprogramming to pluripotency (SCRP). We identified Netrin-1 and its dependence receptor Dcc (Deleted in Colorectal Carcinoma), previously described for their respective survival/death functions both in normal and oncogenic contexts, as novel key SCRP modulators. We show that the early phase of SCRP is accompanied with a strong Netrin-1 deficiency, due to the improper epigenetic regulation of the Ntn1 promoter by OSKM. Mechanistically, we demonstrate that such Netrin-1 imbalance induces apoptosis mediated by the dependence receptor Dcc in a p53-independent manner. Correction of the Netrin-1/Dcc equilibrium by gain-of-ligand and loss-of-receptor experiments constrains apoptosis and improves reprogramming. As a consequence, we propose a novel iPS derivation protocol including a sequential treatment with recombinant Netrin1 that greatly facilitates the generation of mouse and human iPS cells.
2015-09-01 | GSE54107 | GEO
Project description:Inhibition of macrophage migration inhibitory factor (MIF) suppresses apoptosis signal-regulating kinase 1 to protect against liver ischemia/reperfusion injury
| PRJNA875660 | ENA
Project description:Background: Hepatic ischemia–reperfusion (I/R) injury is a major complication leading to surgical failures in liver resection, transplantation, and hemorrhagic shock. The role of cytokine macrophage migration inhibitory factor (MIF) in hepatic I/R injury is unclear. Methods: We examined changes of MIF expression in mice after hepatic I/R surgery and hepatocytes challenged with hypoxia–reoxygenation (H/R) insult. Subsequently, MIF global knock-out mice and mice with adeno-associated-virus (AAV)-delivered MIF overexpression were subjected to hepatic I/R injury. Hepatic histology, the inflammatory response, apoptosis and oxidative stress were monitored to assess liver damage. The molecular mechanisms of MIF function were explored in vivo and in vitro. Results: MIF was significantly upregulated in the serum whereas decreased in liver tissues of mice after hepatic I/R injury. MIF knock-out effectively attenuated I/R -induced liver inflammation, apoptosis and oxidative stress in vivo and in vitro, whereas MIF overexpression significantly aggravated liver injury. Via RNA-seq analysis, we found a significant decreased trend of MAPK pathway in MIF knock-out mice subjected hepatic I/R surgery. Using the apoptosis signal-regulating kinase 1 (ASK1) inhibitor NQDI-1 we determined that, mechanistically, the protective effect of MIF deficiency on hepatic I/R injury was dependent on the suppressing of the ASK1-JNK/P38 signaling pathway. Moreover, we found MIF inhibitor ISO-1 alleviate hepatic I/R injury in mice. Conclusion: Our results confirm that MIF deficiency suppresses the ASK1-JNK/P38 pathway and protects the liver from I/R -induced injury. Our findings suggest MIF as a novel biomarker and therapeutic target for the diagnosis and treatment of hepatic I/R injury.. We then performed gene expression profiling analysis using data obtained from RNA-seq of 6 different liver tissues of mice subjected to hepatic I/R injury.
2022-09-28 | GSE212508 | GEO
Project description:Analysis of microarray data from fetal pancreatic cells 24 hr after exposure to Netrin-4 revealed changes in the expression of several genes relevant to cell cycle control, and differentiation and development.
2011-05-12 | E-TABM-867 | biostudies-arrayexpress