C/EBPβ regulates lipid metabolism and Pparg isoform 2 expression in alveolar macrophages
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE173970 | GEO | 2022/09/16
REPOSITORIES: GEO
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Project description:Pulmonary alveolar proteinosis (PAP) results from a dysfunction of alveolar macrophages (AMs), chiefly due to disruptions in the signaling of granulocyte macrophage colony-stimulating factor (GM-CSF). We found that mice deficient for the B lymphoid transcription repressor BTB and CNC homology 2 (Bach2) developed PAP-like accumulation of surfactant proteins in the lungs. Bach2 was expressed in AMs, and Bach2-deficient AMs showed alterations in lipid handling in comparison with wild-type (WT) cells. Although Bach2-deficient AMs showed a normal expression of the genes involved in the GM-CSF signaling, they showed an altered expression of the genes involved in chemotaxis, lipid metabolism, and alternative M2 macrophage activation with increased expression of Ym1 and arginase-1, and the M2 regulator Irf4. Peritoneal Bach2-deficient macrophages showed increased Ym1 expression when stimulated with interleukin-4. More eosinophils were present in the lung and peritoneal cavity of Bach2-deficient mice compared with WT mice. The PAP-like lesions in Bach2-deficient mice were relieved by WT bone marrow transplantation even after their development, confirming the hematopoietic origin of the lesions. These results indicate that Bach2 is required for the functional maturation of AMs and pulmonary homeostasis, independently of the GM-CSF signaling. WT (n=8) and Bach2KO (n=3) AMs. One expreriment was performed.
2014-01-15 | E-GEOD-54050 | biostudies-arrayexpress
Project description:Tissue resident macrophages show their specific function to maintain homeostasis in our body. Dysfunction of alveolar macrophages (AMs), which regulate the proper amount of surfactant protein, leads to the development of pulmonary alveolar proteinosis (PAP). Here we found that inflammation ruins the function of AMs and is one of the causes of secondary PAP. Inflammation leads to the loss of specific gene expression pattern of AMs and furthermore, it leads to gain the specific gene expression pattern of other tissue resident macrophages and DC lineage. We also found the critical roles for Bach2 expressed in AMs and T cells, whose expression is induced by IFNg released from T cells. Bach2 bounds to super-enhancer regions of the inflammatory genes of the myeloid lineage and represses excess inflammation in lungs. Our results suggest that Bach2 function among several cell lineages to modify the inflammation, maintaining homeostasis in lungs.
2018-11-05 | GSE79023 | GEO
Project description:Pulmonary alveolar proteinosis (PAP) results from a dysfunction of alveolar macrophages (AMs), chiefly due to disruptions in the signaling of granulocyte macrophage colony-stimulating factor (GM-CSF). We found that mice deficient for the B lymphoid transcription repressor BTB and CNC homology 2 (Bach2) developed PAP-like accumulation of surfactant proteins in the lungs. Bach2 was expressed in AMs, and Bach2-deficient AMs showed alterations in lipid handling in comparison with wild-type (WT) cells. Although Bach2-deficient AMs showed a normal expression of the genes involved in the GM-CSF signaling, they showed an altered expression of the genes involved in chemotaxis, lipid metabolism, and alternative M2 macrophage activation with increased expression of Ym1 and arginase-1, and the M2 regulator Irf4. Peritoneal Bach2-deficient macrophages showed increased Ym1 expression when stimulated with interleukin-4. More eosinophils were present in the lung and peritoneal cavity of Bach2-deficient mice compared with WT mice. The PAP-like lesions in Bach2-deficient mice were relieved by WT bone marrow transplantation even after their development, confirming the hematopoietic origin of the lesions. These results indicate that Bach2 is required for the functional maturation of AMs and pulmonary homeostasis, independently of the GM-CSF signaling.
2014-01-15 | GSE54050 | GEO
Project description:Background: Pulmonary alveolar proteinosis (PAP) is a rare disease showing excess accumulation of surfactant protein in the alveolar spaces. It chiefly results from a dysfunction of alveolar macrophages (AMs) due to a lack of granulocyte macrophage colony-stimulating factor (GM-CSF) signaling including the expression of PU.1. We previously reported that mice deficient for Bach2 developed PAP-like disease due to a defect of lipid handling by AMs. Recently, Bach1 and Bach2 have been reported to function redundantly in early B cell development. The aim of this study was to investigate the function of Bach1 and Bach2 in alveolar macrophage and lung homeostasis. Methods: We generated mice lacking both Bach1 and Bach2 (Bach1/2 DKO mice) and investigated their body weight and survival rate. Whole lungs of mice were observed with Hematoxylin and eosin (HE) stain when they were 8 or 12-13 weeks old. The expression of surface markers and the numbers of alveolar macrophages and eosinophils in BAL were analyzed by flow cytometry (FACS). We also analyzed tissue macrophages in bone marrow and spleen by FACS. We administered N-acetyl cysteine to mice from prenatal stage and observed lung pathology at 12 weeks. Result: Bach1/2 DKO mice showed a more rapid and severe PAP phenotype than Bach2-deficient mice (Bach2 KO mice), whereas Bach1-deficient mice (Bach1 KO mice) did not develop any pulmonary disease. AMs in Bach1/2 DKO mice showed a foamy appearance, suggesting a defect in lipid handling. In contrast, the numbers of bone marrow macrophages and red pulp macrophages were not affected in Bach1/2 DKO mice. The PAP-like disease in Bach1/2 DKO and Bach2 KO mice was not ameliorated by N-acetyl cysteine. Conclusion: We suggest that Bach1 and Bach2 work in a complementary manner for the normal function of AMs and the maintenance of surfactant homeostasis in the lungs. Oxidative stress may be involved in the process of PAP by inactivating Bach1 and Bach2.
2018-11-05 | GSE79138 | GEO
Project description:The rapid transit from hypoxia to normoxia in the lung that follows the first breath in newborn mice coincides with alveolar macrophage (AM) differentiation. However, whether sensing of oxygen affects AM maturation and function has not been previously explored. We have generated mice whose AMs show a deficient ability to sense oxygen after birth by deleting Vhl, a negative regulator of HIF transcription factors, in the CD11c compartment (CD11c∆Vhl mice). VHL-deficient AMs show an immature-like phenotype and an impaired self-renewal capacity in vivo that persists upon culture ex vivo. VHL-deficient phenotype is intrinsic in AMs derived from monocyte precursors in mixed bone marrow chimeras. Moreover, unlike control Vhlfl/fl, AMs from CD11c∆Vhl mice do not revert pulmonary alveolar proteinosis when transplanted into Csf2rb-/- mice, demonstrating that VHL contributes to AM-mediated surfactant clearance. Thus, our results suggest that optimal AM terminal differentiation, self-renewal, and homeostatic function requires their oxygen sensing capacity.
2018-06-27 | GSE108975 | GEO
Project description:C/EBPβ plays a major role in numerous biological processes but unfortunately its precise role is not still clear and conflicting studies showed that this transcription factor could have contradictory functions. These latter arise from the complexity of mechanisms regulating C/EBPβ activity. Indeed, C/EBPβ encodes an intronless gene that generates a single mRNA that is alternatively translated into two major isoforms of 35kDa (liver-enriched activator protein: LAP) and 20kDa (liver-enriched inhibitory protein: LIP). LAP is the active isoform of this transcription factor whereas LIP, a truncated isoform negatively regulate C/EBPβ-LAP-mediated gene expression. The main goal of our research was to understand how LAP and LIP isoforms governe C/EBPβ cellular functions with the identification of new genes and pathways regulated by these isoforms in the human Hep3B hepatoma cell line. For this purpose an original in vitro system characterized by a target genes induction with the activatory C/EBPß isoform LAP and a target genes repression with the inhibitory C/EBPß isoform (LIP) was used to identify the genuine C/EBPβ molecular signature. Using a cDNA microarray which provides a complete coverage of the liver transcriptome, we identified 676 genes inversely regulated by LAP and LIP. These selected genes are involved in many biological processes as the hepatic metabolism (cholesterol), detoxification, induction of apoptosis and negative regulation of the cell proliferation. According to the involvement of C/EBPβ in hepatic carcinogenesis we focused on cell cycle regulation and apoptosis. Through functional studies, we proved for the first time that LIP plays in favor of the survival of the Hep3B cells whereas LAP makes the cells more sensitive to staurosporine-induced cell death. Moreover, a lot of studies demonstrated that the anti-proliferative action of C/EBPβ mainly depends on RB protein. By studying the rate of Hep3B cells proliferation which overexpress LAP, we brought to the fore that this isoform would be able to induce a repression of the Hep3B cells line proliferation - a RB- and p53- negative cell line. Thus, LAP seems able to induce the repression of proliferation by a different metabolic way from the RB one. Keywords: comparison of cells expressing LAP or LIP RNA were extracted from 5 Hep3BLAPexpressing LAP, 5 Hep3BLAP control without expression of LAP, 5 Hep3BLIP expressing LIP and 5 Hep3BLIP control without epression of LIP. Each sample was hybridized once in 5 different nylon membranes.
2011-01-16 | E-GEOD-12410 | biostudies-arrayexpress
Project description:<p>The purpose of this study is to (1) compare a technically improved assay with an existing assay used to measure serum anti-GM-CSF antibodies in stored serum samples previously obtained from patients diagnosed with either primary, secondary, congenital or idiopathic pulmonary alveolar proteinosis (PAP), other chronic diseases or disease-free, healthy individuals; (2) determine the prevalence and levels of anti-GM-CSF autoantibodies and (3) define the breadth of the autoimmune antibody responses in primary PAP patients from the United States, Japan, Australia, and Europe using previously collected serum samples; and (4) using a chart review approach, compare the clinical, radiologic and laboratory features of primary PAP patients to determine if differences exist among patients in these globally geographically distributed regions.</p>
| phs001309 | dbGaP
Project description:C/EBPβ plays a major role in numerous biological processes but unfortunately its precise role is not still clear and conflicting studies showed that this transcription factor could have contradictory functions. These latter arise from the complexity of mechanisms regulating C/EBPβ activity. Indeed, C/EBPβ encodes an intronless gene that generates a single mRNA that is alternatively translated into two major isoforms of 35kDa (liver-enriched activator protein: LAP) and 20kDa (liver-enriched inhibitory protein: LIP). LAP is the active isoform of this transcription factor whereas LIP, a truncated isoform negatively regulate C/EBPβ-LAP-mediated gene expression. The main goal of our research was to understand how LAP and LIP isoforms governe C/EBPβ cellular functions with the identification of new genes and pathways regulated by these isoforms in the human Hep3B hepatoma cell line. For this purpose an original in vitro system characterized by a target genes induction with the activatory C/EBPß isoform LAP and a target genes repression with the inhibitory C/EBPß isoform (LIP) was used to identify the genuine C/EBPβ molecular signature. Using a cDNA microarray which provides a complete coverage of the liver transcriptome, we identified 676 genes inversely regulated by LAP and LIP. These selected genes are involved in many biological processes as the hepatic metabolism (cholesterol), detoxification, induction of apoptosis and negative regulation of the cell proliferation. According to the involvement of C/EBPβ in hepatic carcinogenesis we focused on cell cycle regulation and apoptosis. Through functional studies, we proved for the first time that LIP plays in favor of the survival of the Hep3B cells whereas LAP makes the cells more sensitive to staurosporine-induced cell death. Moreover, a lot of studies demonstrated that the anti-proliferative action of C/EBPβ mainly depends on RB protein. By studying the rate of Hep3B cells proliferation which overexpress LAP, we brought to the fore that this isoform would be able to induce a repression of the Hep3B cells line proliferation - a RB- and p53- negative cell line. Thus, LAP seems able to induce the repression of proliferation by a different metabolic way from the RB one. Keywords: comparison of cells expressing LAP or LIP
2011-01-16 | GSE12410 | GEO
Project description:To uncover potential mechanisms underlying the observed Pulmonary Alveolar Proteinosis-like phenotype, we performed a microarray analysis using lung mRNAs from T-bet transgenic mice. Gene expression signatures associated with pulmonary alveolar proteinosis induced by T-bet overexpression in T cells were measured.
2014-11-03 | E-GEOD-62637 | biostudies-arrayexpress
Project description:Tissue-resident macrophage-based immune therapies have been proposed for various diseases. However, generation of sufficient numbers that possess tissue-specific functions remains a major handicap. Here, we show that fetal liver monocytes cultured with GM-CSF (CSF2-cFLiMo) rapidly differentiate into a long-lived, homogeneous alveolar macrophage (AM)-like population in vitro. CSF2-cFLiMo remained the capacity to develop into bona fide AM upon transfer into Csf2ra-/- neonates and prevented development of alveolar proteinosis and accumulation of apoptotic cells for at least 1 year in vivo. CSF2-cFLiMo more efficiently engrafted empty AM niches in the lung and protected mice from severe pathology induced by respiratory viral infection, compared to transplantation of macrophages derived from bone marrow cells cultured with M-CSF (CSF1-cBMM) in the presence or absence of GM-CSF. Harnessing the potential of this approach for gene therapy, we restored a disrupted Csf2ra gene in FLiMo and demonstrated their capacity to develop into AM in vivo. Together, we provide a novel platform for generation of immature AM-like precursors amenable for genetic manipulation, which will be useful to dissect AM development and function and pulmonary transplantation therapy.
2022-01-15 | GSE193537 | GEO