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Von Hippel-Lindau protein is required for optimal alveolar macrophage terminal differentiation, self-renewal and function.

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE108975 | GEO | 2018/06/27

REPOSITORIES: GEO

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Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function.

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

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2019-06-12 | GSE132185 | GEO

Single cell RNA sequencing reveals mechanisms underlying a senescence-like phenotype of Alveolar Macrophages during Aging

Project description:Alveolar Macrophages (AMs) are unique innate immune cells that reside in the alveolar space and accommodate the ever-changing needs of the lungs against internal and external challenges. During homeostasis, AMs maintain themselves through self-renewal without input from adult hematopoietic stem cells. Currently, little is known regarding the influence of aging on AM dynamics, heterogeneity and transcriptional profiles. Here, we identified CBFβ as an indispensable transcription factor that ensures AM self-renewal. Deficiency in CBFβ led to decreased proliferation and self-renewal ability of AMs. Moreover, with single cell RNA sequencing analysis of AMs from young and aged mice, we discovered that despite similarities in the transcriptome of proliferating cells, AMs from the aged mice exhibited reduced embryotic stem cell-like features. Aged AMs also showed diminished capacity for DNA repair, potentially contributing to impaired cell cycle progression and elevation of senescence markers. In accordance with the analysis, we observed reduced number of AMs in aged mice, which had defective self-renewal ability and were more sensitive to the reduction of GM-CSF. Interestingly, decreased CBFβ was observed in the cytosol of AMs from aged mice. A similar senescence-like phenotype was also found in human AMs. Taken together, we conclude that AMs in the aged host harbor a senescence-like phenotype, potentially mediated by the activity of CBFβ.

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RNA expression data from kidneys lacking von Hippel-Lindau (VHL) protein in tubular epithelial cells

Project description:The cellular response to low oxygen supply is mediated by hypoxia-inducible factors (HIF). Under hypoxic conditions, HIF is stabilized and target genes are induced. Under normoxia, however, HIF is ubiquitinated through the von Hippel-Lindau protein (VHL), which results in proteasomal degradation. HIF activation leads to induction of genes involved in erythropoiesis, angiogenesis, and cell survival. Furthermore, HIF orchestrates a metabolic shift from oxidative phosphorylation to glycolysis to facilitate ATP production under low oxygen conditions. We used microarrays to detail gene expression changes in kidneys with stable HIF activation in renal tubules, which was achieved by tubule-specific VHL ablation. Three week old Pax8-rtTA;LC-1;Vhl-floxed mice (n=4) and control littermates (n=4) were treated with doxycyline in drinking water for two weeks and put back on normal drinking water for one week. Six weeks old mice were sacrificed and kidneys harvested. Total RNA was extracted and hybridized on Affymetrix microarrays.

2014-01-17 | E-GEOD-54172 | biostudies-arrayexpress

RNA-seq of mouse alveolar macrophages sorted from CD11cCre/+ Tgfbr2fl/fl and control Tgfbr2fl/fl neonatal mice

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2017-11-08 | E-MTAB-6028 | biostudies-arrayexpress

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2021-03-01 | GSE167349 | GEO

Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function.

2014-01-15 | GSE54050 | GEO

Bach2 keeps homeostasis in lung by regulating inflammatory response and maintaining function of alveolar macrophage.

Project description:Alveolar macrophages (AMs) of Bach2 KO mice show multiple alternations in their functions including lipid metabolism. We aimed to clarify the mechanism whereby deficiency of Bach2 impairs the function of AMs and ruins the homeostasis of lungs. Now we report that some cytokines produced from Bach2-deficient T cells alter the character of AMs and expression of Bach2 is necessary for AMs to maintain the function of lipid metabolism.

2019-02-04 | GSE79558 | GEO

Oxygen sensitive regulation of TFAM linking the von Hippel-Lindau cancer syndrome to impaired mitochondrial biogenesis

Project description:The major consumers of oxygen in the cell are mitochondria. Here we identified an oxygen-sensitive regulation of TFAM, a key activator of mitochondrial transcription and replication. TFAM is hydroxylated by EglN3 on proline 53/56 and subsequently bound by the tumor suppressor von Hippel Lindau (pVHL). pVHL binding stabilizes TFAM by preventing mitochondrial LON proteolysis. Cells lacking wild-type VHL or in which EglN3 was inactivated genetically or by lack of oxygen have reduced mitochondria. All VHL cancer syndrome mutations tested, type 1, 2A, 2B, 2C, failed to bind hydroxylated TFAM, regardless of whether they have the ability to bind hydroxylated HIFa or not. In contrast, VHL-R200W polycythemia-mutation bound hydroxylated TFAM similar as wild-type VHL. VHL-R200W causes polycythemia with total absence of tumor development, despite increased HIFa signaling. Tumors of VHL related malignancies such as pheochromocytoma and renal carcinoma cells show low mitochondrial content, implicating that impaired mitochondrial biogenesis is linked to the malignancies of the VHL hereditary cancer syndrome.

2022-05-25 | PXD022734 | Pride

RNA expression data from kidneys lacking von Hippel-Lindau (VHL) protein in tubular epithelial cells

2014-01-17 | GSE54172 | GEO

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