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Gene expression profiles of CEBPβ-overexpressed alveolar macrophages after A20-Ad treatment

ABSTRACT: Although recent progressions have provided significant mechanistic insights into the pathogenesis of pulmonary fibrosis (PF), few of anti-PF therapeutics show certain promise for this devastating disease. Chronic or repeated lung injury results in chronic inflammation, which functions as a major driven force to promote PF development. Here we report that chronic lung injury inactivates ubiquitin-modifying enzyme A20 to cause a progressive accumulation of transcription factor C/EBPb in macrophages, which produce a number of pro-fibrotic factors to promote PF development. Elevated GSK-3b expression, in response to chronic lung injury, interacts with and phosphorylates A20 to suppress C/EBPb degradation in macrophages. Enforced expression of A20 or pharmacological acceleration of C/EBPb degradation by a peptide restores the A20 activity and provides potent therapeutic efficacy against experimental PF. Our studies reveal a regulatory mechanism of the GSK-3b-A20-C/EBPb axis in alveolar macrophages, by targeting which can treat PF and fibroproliferative lung diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE117690 | GEO | 2018/10/01

REPOSITORIES: GEO

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Gene expression profiles of alveolar macrophages isolated from wild type (WT) and A20 conditional knockout mice after BLM exposure

Project description:Although recent progressions have provided significant mechanistic insights into the pathogenesis of pulmonary fibrosis (PF), few of anti-PF therapeutics show certain promise for this devastating disease. Chronic or repeated lung injury results in chronic inflammation, which functions as a major driven force to promote PF development. Here we report that chronic lung injury inactivates ubiquitin-modifying enzyme A20 to cause a progressive accumulation of transcription factor C/EBPb in macrophages, which produce a number of pro-fibrotic factors to promote PF development. Elevated GSK-3b expression, in response to chronic lung injury, interacts with and phosphorylates A20 to suppress C/EBPb degradation in macrophages. Enforced expression of A20 or pharmacological acceleration of C/EBPb degradation by a peptide restores the A20 activity and provides potent therapeutic efficacy against experimental PF. Our studies reveal a regulatory mechanism of the GSK-3b-A20-C/EBPb axis in alveolar macrophages, by targeting which can treat PF and fibroproliferative lung diseases.

2018-10-01 | GSE117649 | GEO

Development of gene expression signatures of murine silicosis in the lung CD45-negative tissue cells from CCR2 knockout mice

Project description:Pulmonary fibrosis (PF) is an intractable disorder with a poor prognosis. Although macrophages are known to promote both the initiation and resolution of lung injury in reversible PF, it remains unclear how macrophages contribute to the progression of chronic PF. The object of this study was to investigate the role of inflammatory monocyte-derived macrophages (MMs) in the transcriptomic signatures of the lung tissue cells from murine progressive PF. We collected CD45-negative lung tissue cells from silica-treated CCR2 knockout and WT mice on days 28, 40 and untreated mice on day 0 post-aspiration and performed global transcriptome analyses using microarray. Data were analyzed by fuzzy c-means or CLICK clustering, gene set enrichment analysis, and network analyses. Global transcriptome analyses revealed that MM deficiency potentiated changes in gene-expression in tissue cells, closely matching trends seen in human chronic PF. Regulatory network analysis of transcriptome data suggested that MM-derived factors, such as tumor necrosis factor-α, were involved in the suppression of tissue remodeling-related gene expression. Overall, these results demonstrate that MMs suppress tissue cell responses and associated pathology in progressive PF.

2016-09-24 | GSE61709 | GEO

Analysis of Gsk-3-Deficient Embryonic Stem Cells Reveals Large-Scale Alterations in Gene Expression

Project description:The two vertebrate Gsk-3 isoforms, Gsk-3a and Gsk-3b, are encoded by distinct genetic loci and exhibit mostly redundant function in murine embryonic stem cells (ESCs). Here we report that deletion of both Gsk-3a and Gsk-3b in mouse ESCs results in significant changes in gene expression. In contrast, deletion of either Gsk-3a or Gsk-3b individually had little effect on gene expression. These data support the notion that Gsk-3 isoforms are functionally redundant in embryonic stem cells. In addition, we did not find the expected upregulation of known Wnt target genes. Our data suggests that Gsk-3-meidated regulation of gene expression in embryonic stem cells is complex, and likely involves affects on numerous signaling pathways. The study was designed to examine the changes in gene expression between wild-type, Gsk-3a-/-, Gsk-3b-/-, and Gsk-3a-/-;Gsk-3b-/- mouse embryonic stem cells.

2011-09-14 | E-GEOD-27395 | biostudies-arrayexpress

microRNA expression profiles of extracellular vehicles released from alveolar macrophage

Project description:Interstitial lung diseases (ILDs) such as idiopathic pulmonary fibrosis (IPF) is diffuse parenchymal lung disorders characterized by varying degrees of inflammation and fibrosis of the lung interstitium. The failure of lung alveolar regeneration in IPF is critical for this incurable disease. Here we report that chronic lung injury causes a profibrotic phenotype of alveolar macrophages that release extracellular vehicles (EVs) to promote PF development through repressing the stemness traits of type 2 alveolar epithelial cells (AEC2s). We found that an increased expression of acetylases KAT5 interacts with and acetylates protein kinase MLKL, which directly promotes release of EVs from AMs following chronic lung injury. AEC2s takes up the EVs and releases miR-148a-3p to repress expression of endogenous b-catennin agonist Wnt10b and alveolar regeneration. Pharmacologic inhibition of the miR-148a-3p expression or interruption of the KAT5-MLKL interaction restores regenerative capacity of AEC2s and exhibits potent therapeutic efficacy against PF. Our study confers a potential strategy for the treatment of IPF and other interstitial lung diseases.

2023-09-01 | GSE184147 | GEO

Role of CCR2+ Myeloid Cells in Inflammatory Responses Driven by Mutation in Surfactant Protein-C Expression

Project description:Acute inflammatory exacerbations (AIE) represent precipitous deteriorations of a number of chronic lung conditions, including pulmonary fibrosis (PF), chronic obstructive pulmonary disease and asthma. AIEs are marked by diffuse and persistent polycellular alveolitis that profoundly accelerate lung function decline and mortality. In particular, excess monocyte mobilization during AIE and their persistence in the lung have been suggested to be linked to poor disease outcome. We have developed a mutant model of pulmonary fibrosis leveraging the PF-linked missense isoleucine to threonine substitution at position 73 [I73T] in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene [SFTPC]. With this toolbox at hand, the present work investigates the dynamics of resident alveolar macrophages and peripheral monocytes during the initiation and progression of AIE-PF. FACS analysis of SigF+CD11b- alveolar macrophages and Ly6Chi monocytes isolated 3 d and 14 d after SP-CI73T injury and performed RNA sequencing. Pathway and gene expression analysis revelaed dynamic transcriptional changes associated with “Innate Immunity’ and ‘Extracellular Matrix Organization’ signaling. Supported by previous pharmacological evidence, genetic ablation of CCR2+ monocytes (SP-CI73TCCR2KO) resulted in improved lung histology, mouse survival, and reduced inflammation compared to SP-CI73TCCR2WT cohorts. Immunohistochemical and in situ hybridization analysis revealed comparable levels of tgfb1 mRNA expression localized primarily parenchymal cells found nearby foci of injury. Our results also confirmed reduced inflammatory activation (iNOS, Arg1) in SP-CI73TCCR2KO lungs as well as partial colocalization of tgfb1 mRNA expression in Arg1+ cells. These results provide a detailed picture on the role of resident macrophages and recruited monocytes in the context of AIE-PF driven by alveolar epithelial dysfunction.

2021-02-07 | GSE166300 | GEO

Analysis of Gsk-3-Deficient Embryonic Stem Cells Reveals Large-Scale Alterations in Gene Expression

2011-09-15 | GSE27395 | GEO

Phosphatidylinositol 3-Kinase (PI3K) Signaling via Glycogen Synthase Kinase-3 (Gsk-3) Regulates DNA Methylation of Imprinted Loci.

Project description:The two vertebrate Gsk-3 isoforms, Gsk-3a and Gsk-3b, are encoded by distinct genetic loci and exhibit mostly redundant function in murine embryonic stem cells (ESCs). Here we report that deletion of both Gsk-3a and Gsk-3b in mouse ESCs results in misregulated expression of imprinted genes and hypomethylation of corresponding imprinted loci. Treatment of wild-type ESCs with small molecule inhibitors of Gsk-3 phenocopies the DNA hypomethylation of imprinted loci observed in Gsk-3 null ESCs. We provide evidence that DNA hypomethylation in Gsk-3 null ESCs is due to a reduction in the levels of the de novo DNA methyltransferase, Dnmt3a2. Gsk-3 activity serves as a node for several signal transduction pathways, and its regulation of Dnmt3a2 expression raises the possibility that DNA methylation could be transiently affected by different types of environmental stimuli. Our data suggest that modulating Gsk-3 activity could have further reaching effects in the regulation of the epigenome. Keywords: Gene expression array-based The study was designed to examine the changes in gene expression between wild-type and Gsk-3a-/-;Gsk-3b-/- mouse embryonic stem cells.

2010-11-15 | E-GEOD-20015 | biostudies-arrayexpress

Expression data from E18 mouse dorsal telencephalon

Project description:Neurons deficient in both GSK-3 alpha and beta isoforms fail to migrate properly and develop abnormal morphology. In exploring mechanisms, we found no change in Wnt transcriptional target genes. Verified decrease in GSK-3B exon 2 RNA was extracted from presumptive somatosensory cortices of E18 GSK-3 alpha -/- beta loxp/loxp (control) and GSK-3:Nex conditional mutant embryos. There were totally 6 samples: 3 control and 3 mutants.

2014-07-29 | E-GEOD-58727 | biostudies-arrayexpress

GSK-3A and GSK-3B knockdown in AML cell lines

Project description:Gene expression data from AML cell lines, MOLM-14, U937, THP-1 and HL-60, that were infected with a scrambled control hairpin (shControl), two shRNAs directed against GSK-3B (shGSK3B_1 and shGSK3B_2), or two shRNAs directed against GSK-3A (shGSK3A_5 and shGSK3A_6). Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetic-based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3A (GSK-3A) in AML by performing two independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3A induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and cell surface markers consistent with myeloid maturation. GSK-3AM-bM-^@M-^Sspecific suppression also led to impaired growth and proliferation in vitro, induction of apoptosis, loss of colony formation in methylcellulose, and anti-AML activity in vivo. Although the role of GSK-3B has been well studied in cancer development, these studies support a role for GSK-3A in AML. The AML cell lines, MOLM-14, U937, THP-1 and HL-60, were infected with a scrambled control hairpin (shControl), two shRNAs directed against GSK-3B (shGSK3B_1 and shGSK3B_2), and two shRNAs directed against GSK-3A (shGSK3A_5 and shGSK3A_6).

2012-02-27 | E-GEOD-35200 | biostudies-arrayexpress

Phosphatidylinositol 3-Kinase (PI3K) Signaling via Glycogen Synthase Kinase-3 (Gsk-3) Regulates DNA Methylation of Imprinted Loci.

Project description:The two vertebrate Gsk-3 isoforms, Gsk-3a and Gsk-3b, are encoded by distinct genetic loci and exhibit mostly redundant function in murine embryonic stem cells (ESCs). Here we report that deletion of both Gsk-3a and Gsk-3b in mouse ESCs results in misregulated expression of imprinted genes and hypomethylation of corresponding imprinted loci. Treatment of wild-type ESCs with small molecule inhibitors of Gsk-3 phenocopies the DNA hypomethylation of imprinted loci observed in Gsk-3 null ESCs. We provide evidence that DNA hypomethylation in Gsk-3 null ESCs is due to a reduction in the levels of the de novo DNA methyltransferase, Dnmt3a2. Gsk-3 activity serves as a node for several signal transduction pathways, and its regulation of Dnmt3a2 expression raises the possibility that DNA methylation could be transiently affected by different types of environmental stimuli. Our data suggest that modulating Gsk-3 activity could have further reaching effects in the regulation of the epigenome. Keywords: Gene expression array-based

2010-11-15 | GSE20015 | GEO

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