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A Genome-Wide CRISPR Screen Identifies DTX4 Modulating Alveolar Macrophage Cholesterol Efflux in Pulmonary Alveolar Proteinosis [RNA-seq 1]

ABSTRACT: Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by impaired surfactant clearance, driven by dysfunctional cholesterol efflux in alveolar macrophages (AMs). However, the molecular determinants governing AM cholesterol homeostasis remain largely elusive. Here, through a genome-wide CRISPR activation screen in foamy macrophages and bulk RNA sequencing of AMs from PAP patients, we identify Deltex E3 Ubiquitin Ligase 4 (DTX4) as a pivotal regulator of cholesterol efflux in AMs. Adeno-associated virus (AAV) -mediated silencing of DTX4 led to excessive lipid accumulation in AMs, exacerbated alveolar proteinosis, increased lung opacities on imaging, and significantly deteriorated pulmonary function in mice. Similarly, DTX4 depletion in primary AMs impaired cholesterol efflux and promoted intracellular lipid deposition. In contrast, AM-specific overexpression of DTX4 markedly alleviated lipid accumulation, mitigated alveolar proteinosis, restored lung densities on computed tomography, and rescued pulmonary function in Csf2ra-/-mice, a model of PAP. Mechanistically, DTX4 deficiency downregulated PPAR-γ expression, driving foamy AM formation. Notably, the regulatory function of DTX4 in lipid homeostasis was partially mediated by PPAR-γ but independent of its canonical E3 ubiquitin ligase activity. Collectively, our findings establish DTX4 as a central orchestrator of AM cholesterol efflux and surfactant homeostasis, positioning it as a promising therapeutic target for PAP and a potential paradigm for cholesterol dysregulation in related disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299689 | GEO | 2026/04/23

REPOSITORIES: GEO

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A Genome-Wide CRISPR Screen Identifies DTX4 Modulating Alveolar Macrophage Cholesterol Efflux in Pulmonary Alveolar Proteinosis [CRISPR]

Project description:Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by impaired surfactant clearance, driven by dysfunctional cholesterol efflux in alveolar macrophages (AMs). However, the molecular determinants governing AM cholesterol homeostasis remain largely elusive. Here, through a genome-wide CRISPR activation screen in foamy macrophages and bulk RNA sequencing of AMs from PAP patients, we identify Deltex E3 Ubiquitin Ligase 4 (DTX4) as a pivotal regulator of cholesterol efflux in AMs. Adeno-associated virus (AAV) -mediated silencing of DTX4 led to excessive lipid accumulation in AMs, exacerbated alveolar proteinosis, increased lung opacities on imaging, and significantly deteriorated pulmonary function in mice. Similarly, DTX4 depletion in primary AMs impaired cholesterol efflux and promoted intracellular lipid deposition. In contrast, AM-specific overexpression of DTX4 markedly alleviated lipid accumulation, mitigated alveolar proteinosis, restored lung densities on computed tomography, and rescued pulmonary function in Csf2ra-/-mice, a model of PAP. Mechanistically, DTX4 deficiency downregulated PPAR-γ expression, driving foamy AM formation. Notably, the regulatory function of DTX4 in lipid homeostasis was partially mediated by PPAR-γ but independent of its canonical E3 ubiquitin ligase activity. Collectively, our findings establish DTX4 as a central orchestrator of AM cholesterol efflux and surfactant homeostasis, positioning it as a promising therapeutic target for PAP and a potential paradigm for cholesterol dysregulation in related disorders.

2026-04-23 | GSE299696 | GEO

A Genome-Wide CRISPR Screen Identifies DTX4 Modulating Alveolar Macrophage Cholesterol Efflux in Pulmonary Alveolar Proteinosis [RNA-seq II]

2026-04-23 | GSE299693 | GEO

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

Double knockout of Bach1 and Bach2 reveals shared compensatory mechanisms in regulating alveolar macrophage function and lung surfactant homeostasis [ChIP-Seq]

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

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

2014-01-15 | GSE54050 | GEO

C/EBPβ regulates lipid metabolism and Pparg isoform 2 expression in alveolar macrophages

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

A Genome-Wide CRISPR Screen Identifies DTX4 Modulating Alveolar Macrophage Cholesterol Efflux in Pulmonary Alveolar Proteinosis [CRISPR]

Project description:A Genome-Wide CRISPR Screen Identifies DTX4 Modulating Alveolar Macrophage Cholesterol Efflux in Pulmonary Alveolar Proteinosis [CRISPR]

| PRJNA1276087 | ENA

Bach2 keeps homeostasis in lung by regulating inflammatory response and maintaining function of alveolar macrophage [array]

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

HIF-1α and HIF-2α transcription factors differentially regulate lung alveolar macrophage function

Project description:Alveolar Macrophages (AMs) reside in the alveoli, therefore maintaining an active degradation of hypoxia-inducible transcription factors (HIF) mediated by Von Hippel-Lindau protein (pVHL). We previously found that Vhl-deficient AMs are immature and functionally impaired. Here we investigated the specific contribution of HIF-1α and HIF-2α isoforms to the regulation of the AM function. Our work demonstrates that in Vhl-deficient macrophages, both HIF-1α and HIF-2α contribute to AM defective self-renewal, while HIF-2α plays a central role in regulating the impaired AM maturation associated with pVHL loss. HIF-1α promotes a glycolytic shift in alveolar macrophages, while HIF-2α hinders lipid oxidation and surfactant clearance. Thus, HIF-2α raises as a selective critical factor restraining the therapeutic potential of AMs to degrade surfactant excess in mice that have developed pulmonary alveolar proteinosis (PAP). Overall, regulation of both HIF-1α and HIF-2α isoforms is required for an optimal AM function.

2026-03-23 | GSE325293 | GEO

A Genome-Wide CRISPR Screen Identifies DTX4 Modulating Alveolar Macrophage Cholesterol Efflux in Pulmonary Alveolar Proteinosis [RNA-seq 1]

Project description:A Genome-Wide CRISPR Screen Identifies DTX4 Modulating Alveolar Macrophage Cholesterol Efflux in Pulmonary Alveolar Proteinosis [RNA-seq 1]

| PRJNA1276074 | ENA

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