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Foxf1 enchances pulmonary inflammation and mastocytosis

ABSTRACT: The Forkhead Box f1 (Foxf1) transcriptional factor (previously known as HFH-8 or Freac-1) is expressed in endothelial and smooth muscle cells in the embryonic and adult lung. To assess effects of Foxf1 during lung injury, we used CCl4 injury model. Foxf1+/- mice developed severe airway obstruction and bronchial edema, associated with increased numbers of pulmonary mast cells and increased mast cell degranulation following injury. Pulmonary inflammation in Foxf1+/- mice was associated with diminished expression of Foxf1, increased mast cell tryptase and increased expression of CXCL12, the latter being essential for mast cell migration and chemotaxis. Foxf1 haploinsufficiency caused pulmonary mastocytosis and enhanced pulmonary inflammation following chemically-induced lung injury, indicating an important role for Foxf1 in the pathogenesis of pulmonary inflammatory responses. Keywords: Influence of genetic modification on the pulmonary inflamation

ORGANISM(S): Mus musculus

PROVIDER: GSE11112 | GEO | 2008/09/04

SECONDARY ACCESSION(S): PRJNA107003

REPOSITORIES: GEO

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Foxf1 enchances pulmonary inflammation and mastocytosis

Project description:The Forkhead Box f1 (Foxf1) transcriptional factor (previously known as HFH-8 or Freac-1) is expressed in endothelial and smooth muscle cells in the embryonic and adult lung. To assess effects of Foxf1 during lung injury, we used CCl4 injury model. Foxf1+/- mice developed severe airway obstruction and bronchial edema, associated with increased numbers of pulmonary mast cells and increased mast cell degranulation following injury. Pulmonary inflammation in Foxf1+/- mice was associated with diminished expression of Foxf1, increased mast cell tryptase and increased expression of CXCL12, the latter being essential for mast cell migration and chemotaxis. Foxf1 haploinsufficiency caused pulmonary mastocytosis and enhanced pulmonary inflammation following chemically-induced lung injury, indicating an important role for Foxf1 in the pathogenesis of pulmonary inflammatory responses. Keywords: Influence of genetic modification on the pulmonary inflamation Foxf1+/- mice in which the Foxf1 allele was disrupted by an in-frame insertion of a nuclear localizing -galactosidase (-Gal) gene were bred for ten generations into the Black Swiss mouse genetic background. Carbon tetrachloride (CCl4; Sigma, St Louis, MO) was dissolved in mineral oil at a 1:20 ratio v/v and a single intraperitoneal (i.p.) injection of CCl4 (0.5 l of CCl4/ 1g of body weight) was administered to male Foxf1+/- mice or their wild type (WT) littermates as described.

2008-09-04 | E-GEOD-11112 | biostudies-arrayexpress

Mus musculus

Project description:Foxf1 enchances pulmonary inflammation and mastocytosis

| PRJNA107003 | ENA

The association of Greig cephalopolysyndactyly syndrome and congenital mastocytosis reveals the hedgehog signaling pathway involvement in mastocytosis development

Project description:Mastocytosis is a heterogeneous disease characterized by an abnormal accumulation of mast cells (MCs) in one or several organs.Although a somatic KIT D816V mutation is detected in ~85% of patients, attempts to demonstrate its oncogenic effect alone have repeatedly failed, suggesting that additional pathways are involved in MC transformation. From three children presenting with both Greig cephalopolysyndactyly syndrome (GCPS, MIM#175700) and congenital mastocytosis, we demonstrated the involvement of the hedgehog (Hh) pathway in mastocytosis. GCPS is an extremely rare syndrome resulting from haploinsufficiency of GLI3, the major repressor of Hh family members. From these familial cases of mastocytosis, we demonstrate that the Hh pathway is barely active in normal primary MCs and overactive in neoplastic MCs and that GLI3 and KITmutations have a synergistic, tumorigenic effect on the onset of mastocytosis in a GCPS mouse model. Finally, we show that Hh inhibitors suppress neoplastic MC proliferation in vitro and extend the survival time of ASM mice. This work revealed, for the first time, the involvement of Hh signaling in the pathophysiology of mastocytosis and demonstrated the cooperative effects of the KIT and Hh oncogenic pathways in ASM, leading to the identification of new promising therapeutic targets.

2021-12-02 | E-MTAB-9893 | biostudies-arrayexpress

FOXF1 inhibits endothelial barrier function in the lung and transcriptionally activates the gene for the S1PR1 receptor

Project description:Multiple signaling pathways, structural proteins and transcription factors are involved in regulation of endothelial barrier function. The Forkhead protein FOXF1 is a key transcriptional regulator of lung embryonic development, and we use a conditional knockout approach to examine the role of FOXF1 in adult lung homeostasis and lung injury and repair. Tamoxifen-regulated deletion of both Foxf1 alleles in endothelial cells of adult mice (Pdgfb-iCreER/Foxf1 caused lung inflammation and edema, leading to respiratory insuffency and uniform mortality. Deletion of a single foxf1 allele was sufficient to increase susceptibility of heterozygous mice to acute lung injury. FOXF1 abundance was decreased in pulmonary endothelial cells of human patients with acute lung injury. Gene expression analysis of pulmonary endothelial cells of FOXF1 deletion indicated reduced expression for genes critical for maintance and regulation of adherens junctions. FOXF1 knockdown in vitro and in vivo disrupted adherens junctions, increased lung endothelial permeability, and the abundance of mRNA and protein for sphingosine 1 phosphate receptor 1 (S1PR1), a key regulator of endothelial barrier function. Chromatin immunoprecipitation and luciferase reporter assay demonstrated that FOXF1 directly bound to and induced the tanscriptional activity of the S1pr1 promoter. Pharmacological administratiion of S1P to injured pdgfb-iCreER/Foxf1 mice restored endothelial barrier function, decreased lung edema and improved survival. Thus, FOXF1 promotes normal lung homeostasis and lung repair, at least in part, by enhancing endothelial barrier function through transcriptional activation of the S1P/S1PR1/ signaling pathway.

2016-04-20 | GSE78184 | GEO

A proteomic and transcriptomic screening demonstrate increased mast cell-derived CCL23 in systemic mastocytosis

Project description:Systemic mastocytosis is a heterogeneous group of mast cell-driven diseases, diagnosed by bone marrow sampling. However, there are a limited number of available blood disease biomarkers. We performed a single-cell transcriptomics screen alongside a plasma proteomics screen to identify such potential biomarkers.

2023-02-27 | GSE222830 | GEO

HPLC-ESI-MS PROFILE OF SALIVARY PROTEINS IN MASTOCYTOSIS PATIENTS

Project description:Mastocytosis is a myeloproliferative neoplasm characterized by infiltration of clonally derived mast cells in different tissues. According to mast cells localization, it is possible to discriminate cutaneous mastocytosis (CM) from systemic mastocytosis (SM), the latter involving at least an extracutaneous organ, like bone marrow, liver, spleen and gastrointestinal tract. Some of the SM patient can develop also cutaneous lesions (SM+C). Disease classification is often tricky. Oral cavity is commonly involved in the symptomatology. With the aim to highlight possible qualitative/quantitative modifications of the salivary proteome associated to the different forms of the disease, we investigated the protein profiles of CM, SM, and SM+C patients, and healthy controls, by integrated top-down platforms. a top-down proteomic platform, based on high performance liquid chromatography separation coupled to electrospray-ion trap mass spectrometry (HPLC-ESI-IT-MS) analysis of the acidic soluble proteome of human saliva, which was standardized in our previous studies for detecting and quantifying of hundreds salivary peptides/proteins. By this approach, it is possible to obtain a profiling of the naturally occurring salivary proteome, including isoforms and post-translational modifications (PTMs), to compare an unlimited number of samples and to quantify proteins aby a label-free method.

2020-06-25 | PXD017759 | Pride

Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling (Human).

Project description:Pulmonary fibrosis results from dysregulated repair of damaged tissue caused by persistent injury of lung epithelium. Multiple cell types in the lung are involved in the process of repair. During lung fibrogenesis, normal endothelial cells (EC) are re-programmed into fibrosis-associated EC. Transcriptional factors that control re-programming are poorly understood. Using single cell RNA-sequencing of EC from donor and idiopathic pulmonary fibrosis (IPF) lungs, and lungs from bleomycin-treated mice, we identified endothelial transcription factors (TF) that were differentially expressed during fibrosis. Focusing on one of endothelial TF, FOXF1, we demonstrated that FOXF1 is decreased in EC within human IPF and mouse bleomycin-injured fibrotic lungs.

2022-09-16 | GSE213017 | GEO

Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling (Mouse I).

2022-09-16 | GSE213016 | GEO

Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling (Mouse II).

2022-09-16 | GSE213279 | GEO

FOXF1 inhibits pulmonary fibrosis by preventing CDH2-CDH11 cadherin switch in myofibroblasts

Project description:Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant accumulation of collagen-secreting myofibroblasts. Development of effective therapies is limited due to incomplete understanding of molecular mechanisms regulating myofibroblast expansion. FOXF1 transcription factor is expressed in resident lung fibroblasts, but its role in lung fibrosis remains unknown due to the lack of genetic mouse models. Through comprehensive analysis of human IPF genomics data, lung biopsies and transgenic mice with fibroblast-specific inactivation of FOXF1, the present study shows that FOXF1 inhibits pulmonary fibrosis. FOXF1 deletion increases myofibroblast invasion, collagen secretion, and promotes a switch from of N-cadherin (CDH2) to Cadherin-11 (CDH11), which is critical step in acquisition of pro-fibrotic phenotype. FOXF1 directly binds to Cdh2 and Cdh11 promoters and differentially regulates transcription of these genes. Re-expression of CDH2 or inhibition of CDH11 in FOXF1-deficient cells reduces myofibroblast invasion in vitro. FOXF1 inhibits pulmonary fibrosis by regulating a switch from CDH2 to CDH11 in lung myofibroblasts.

2018-08-09 | GSE110408 | GEO

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