Bach2 keeps homeostasis in lung by regulating inflammatory response and maintaining function of alveolar macrophage.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE79558 | GEO | 2019/02/04
REPOSITORIES: GEO
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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. WT (n=8) and Bach2KO (n=3) AMs. One expreriment was performed.
2014-01-15 | E-GEOD-54050 | biostudies-arrayexpress
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:Bach2 codes for a transcriptional regulator exerting major influences on T cell mediated immune regulation. Effector CTLs derived from in vitro activation of murine CD8+ T cells showed increased proliferative and cytolytic capacity in the absence of BACH2. Before activation, BACH2-deficient CD8+ T cells had a higher abundance of memory and reduced abundance of naïve cells compared to wild-type. CTLs derived from central memory T cells were more potently cytotoxic than those derived from naïve T cells, but even within separated subsets, BACH2-deficiency conferred a cytotoxic advantage. Immunofluorescence and electron microscopy revealed larger granules in BACH2-deficient compared to wild-type CTLs, and proteomic analysis showed an increase in granule content, including perforin and granzymes. Thus, the enhanced cytotoxicity observed in effector CTLs lacking BACH2 arises not only from differences in their initial differentiation state but also inherent production of enlarged cytolytic granules. These results demonstrate how a single gene deletion can produce a CTL super-killer.
2022-09-02 | PXD036457 | Pride
Project description:It is becoming clear that the acquisition of T cell functions is closely linked to the reprogramming of the metabolic pathway. However, the impact of metabolic changes on the differentiation of helper T cell subsets remains unclear. We herein demonstrate a critical role of glutamine metabolism in regulating type 2-immune response. Bach2, a transcriptional repressor, binds to an AP-1 motif, and suppresses Th2 cell differentiation and glutaminolysis. Glutaminase 2, which controls glutamine metabolism, was identified as a Bach2 target gene. The pharmacological inhibition of glutamine metabolism normalized allergic lung inflammation that developed spontaneously in T-cell specific Bach2-deficient mice. These findings reveal the importance of the Bach2-dependent modulation of glutamine metabolism in regulating Th2 cell differentiation and Th2 cell- mediated inflammation.
2016-11-14 | GSE65083 | GEO
Project description:It is becoming clear that the acquisition of T cell functions is closely linked to the reprogramming of the metabolic pathway. However, the impact of metabolic changes on the differentiation of helper T cell subsets remains unclear. We herein demonstrate a critical role of glutamine metabolism in regulating type 2-immune response. Bach2, a transcriptional repressor, binds to an AP-1 motif, and suppresses Th2 cell differentiation and glutaminolysis. Glutaminase 2, which controls glutamine metabolism, was identified as a Bach2 target gene. The pharmacological inhibition of glutamine metabolism normalized allergic lung inflammation that developed spontaneously in T-cell specific Bach2-deficient mice. These findings reveal the importance of the Bach2-dependent modulation of glutamine metabolism in regulating Th2 cell differentiation and Th2 cell- mediated inflammation.
2016-11-14 | GSE63380 | GEO
Project description:Immaturity of alveolar macrophages (AMs) around birth contributes to the susceptibility of newborns to lung disease. However, the molecular features differentiating neonatal and mature, adult AMs are poorly understood. Here we identify the unique transcriptomes and enhancer landscapes of neonatal and adult AMs. While the core AM signature was similar, adult AMs expressed higher levels of genes involved in lipid metabolism, while neonatal AMs expressed a largely proinflammatory gene profile. Open enhancer regions identified by ATAC-seq contained motifs for nuclear receptors, MITF, and STAT in adult AMs and AP-1 and NF-kB in neonatal AMs. Intranasal LPS activated a similar innate immune response in both neonates and adults, with higher basal expression of inflammatory genes in neonates. The lung microenvironment drove many of the distinguishing gene expression and open chromatin characteristics of neonatal and adult AMs. Neonatal AMs retained high expression of some proinflammatory genes, suggesting the differences in neonatal AMs result from both inherent cell properties and environmental influences.
2022-07-05 | GSE196926 | GEO
Project description:In this report, we showed that TFAM deficiency caused impaired AM mitochondrial fitness, altered metabolism and defective lipid catabolic responses, leading to diminished AM quantity and altered AM phenotypes. We demonstrated that TFAM deficiency did not impair AM differentiation from their precursors, but caused reduced AM maintenance. RNA-seq experiment revealed that TFAM deficiency caused impaired AM self-renewal capability. We showed that TFAM deficiency in AMs caused impaired clearance of respiratory debris, surfactant and enhanced susceptibility to severe influenza virus infection. Finally, we found that influenza infection resulted in disruption of TFAM-mediated mitochondrial fitness and metabolism in AMs.
2021-11-07 | GSE188279 | GEO
Project description:Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by accumulation of surfactant lipoproteins within the lung alveoli. Alveolar macrophages (AMs) are crucial for surfactant clearance and their differentiation depends on colony-stimulating factor 2 (CSF2) and the establishment of an AM-characteristic gene regulatory network. Here we report that the transcription factor C/EBPβ is essential for the development of the AM identity, as demonstrated by transcriptome and chromatin accessibility analysis. Furthermore, C/EBPβ-deficient AMs showed severe defects in proliferation, phagocytosis and lipid metabolism, collectively resulting in a PAP-like syndrome. Mechanistically, the long C/EBPβ protein variants LAP* and LAP together with CSF2 signaling induced expression of Pparg isoform2, but not isoform1, a molecular regulation that was also observed in other CSF2-primed macrophages. These results uncover C/EBPβ as a key regulator of AM cell fate and as the missing link between CSF2 and Pparg isoform 2 expression, thereby regulating lipid turnover in AMs.
2022-09-16 | GSE173970 | GEO