CFTR modulator therapy enhances peripheral blood monocyte contributions to immune responses in people with cystic fibrosis
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PROVIDER: PRJNA623007 | ENA |
REPOSITORIES: ENA
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Project description:Background: CFTR modulators will decrease some etiologies of inflammation in the CF airway; however, current data indicate that non-resolving airway infection and inflammation will persist in individuals with CF and chronic bacterial infections. Thus, identification of therapies that diminish CF airway inflammation without allowing unrestrained bacterial growth remains a critical research goal. Novel strategies for combatting deleterious airway inflammation require a better understanding of the cellular contributions to chronic CF airway disease, and how cells change after initiation of CFTR modulator therapy. Peripheral blood monocytes, which traffic to the CF airway, can develop both pro-inflammatory and inflammation-resolving phenotypes, and represent intriguing targets for focused therapies to dampen CF airway inflammation. Material and Methods: In order to characterize the inflammatory phenotype of CF blood monocytes, and how these cells change after initiation of CFTR modulator therapy, we studied adults (n=10) with CF, chronic airway infections, and the CFTR-R117H mutations before and 7 days after initiation of ivacaftor. Transcriptomes of freshly isolated blood monocytes were interrogated by RNA-sequencing (RNA-seq). Plasma concentrations of cytokines and chemokines were evaluated by multiplex ELISA. Results: RNAseq identified approximately 50 monocyte genes for which basal expression was significantly changed in all 10 subjects after 7 days of ivacaftor. Of these, the majority were increased in expression post ivacaftor, including many genes traditionally associated with enhanced inflammation and immune responses. Pathway analyses confirmed that transcriptional pathways were overwhelmingly up-regulated in monocytes after 7 days of ivacaftor, including transcriptional modules associated with immunity, cell cycle, oxidative phosphorylation, and the unfolded protein response. Ivacaftor increased plasma concentrations of CXCL2, a neutrophil chemokine secreted by monocytes and macrophages, and CCL2, a monocyte chemokine. These results demonstrate that ivacaftor causes acute changes in blood monocytes and plasma chemokines, and suggest that increased monocyte inflammatory signals and potentially improved trafficking to the lung contribute to changes in airway inflammation in people taking CFTR modulators. To our knowledge, this is the first report investigating the transcriptomic response of isolated blood monocytes in CF subjects.
2020-07-31 | GSE148076 | GEO
Project description:Production of functional proteins requires multiple steps including gene transcription and post-translational processing. MicroRNAs (miRNA) can regulate individual stages of these processes. Despite the importance of the cystic fibrosis transmembrane conductance regulator (CFTR) channel for epithelial anion transport, how its expression is regulated remains uncertain. We discovered that microRNA-138 regulates CFTR expression through its interactions with the transcriptional regulatory protein SIN3A. Treating airway epithelia with a miR-138 mimic increased CFTR mRNA and also enhanced CFTR abundance and transepithelial Cl- permeability independently of elevated mRNA levels. A miR-138 anti-miR had the opposite effects. Importantly, miR-138 altered the expression of many genes encoding proteins that associate with CFTR and may influence its biosynthesis. The most common CFTR mutation, M-NM-^TF508, causes protein misfolding, degradation, and cystic fibrosis. Remarkably, manipulating the miR-138 regulatory network also improved biosynthesis of CFTR-M-NM-^TF508 and restored Cl- transport to cystic fibrosis airway epithelia. This novel miRNA-regulated network directs gene expression from the chromosome to the cell membrane, indicating that an individual miRNA can control a cellular process broader than previously recognized. This discovery also provides new therapeutic avenues for restoring CFTR function to cells affected by the most common cystic fibrosis mutation. 12 samples of Calu-3 cells representing different interventions.
2012-09-04 | E-GEOD-38956 | biostudies-arrayexpress
Project description:The purpose of this study was to explore baseline expression of miRNome in Cystic Fibrosis Bronchial Epithelial (CFBE41o-) cells stably transfected with wild type (WT) Cystic Fibrosis Transmembrane Conductance regulator (CFTR) and F508del-CFTR. To fulfill this goal miRNA sequencing was done to see miRNA landscape in CFBE41o- Cells with homozygous F508del mutated CFTR and in CFBE41o- Cells with homozygous WT-CFTR, without any treatment condition.
2019-03-28 | GSE128912 | GEO
Project description:Production of functional proteins requires multiple steps including gene transcription and post-translational processing. MicroRNAs (miRNA) can regulate individual stages of these processes. Despite the importance of the cystic fibrosis transmembrane conductance regulator (CFTR) channel for epithelial anion transport, how its expression is regulated remains uncertain. We discovered that microRNA-138 regulates CFTR expression through its interactions with the transcriptional regulatory protein SIN3A. Treating airway epithelia with a miR-138 mimic increased CFTR mRNA and also enhanced CFTR abundance and transepithelial Cl- permeability independently of elevated mRNA levels. A miR-138 anti-miR had the opposite effects. Importantly, miR-138 altered the expression of many genes encoding proteins that associate with CFTR and may influence its biosynthesis. The most common CFTR mutation, ΔF508, causes protein misfolding, degradation, and cystic fibrosis. Remarkably, manipulating the miR-138 regulatory network also improved biosynthesis of CFTR-ΔF508 and restored Cl- transport to cystic fibrosis airway epithelia. This novel miRNA-regulated network directs gene expression from the chromosome to the cell membrane, indicating that an individual miRNA can control a cellular process broader than previously recognized. This discovery also provides new therapeutic avenues for restoring CFTR function to cells affected by the most common cystic fibrosis mutation.
2012-09-04 | GSE38956 | GEO
Project description:BackgroundCFTR modulators decrease some etiologies of CF airway inflammation; however, data indicate that non-resolving airway infection and inflammation persist in individuals with CF and chronic bacterial infections. Thus, identification of therapies that diminish airway inflammation without allowing unrestrained bacterial growth remains a critical research goal. Novel strategies for combatting deleterious airway inflammation in the CFTR modulator era require better understanding of cellular contributions to chronic CF airway disease, and how inflammatory cells change after initiation of CFTR modulator therapy. Peripheral blood monocytes, which traffic to the CF airway, can develop both pro-inflammatory and inflammation-resolving phenotypes, represent intriguing cellular targets for focused therapies. This therapeutic approach, however, requires a more detailed knowledge of CF monocyte cellular programming and phenotypes.Material and methodsIn order to characterize the inflammatory phenotype of CF monocytes, and how these cells change after initiation of CFTR modulator therapy, we studied adults (n=10) with CF, chronic airway infections, and the CFTR-R117H mutations before and 7 days after initiation of ivacaftor. Transcriptomes of freshly isolated blood monocytes were interrogated by RNA-sequencing (RNA-seq) followed by pathway-based analyses. Plasma concentrations of cytokines and chemokines were evaluated by multiplex ELISA.ResultsRNAseq identified approximately 50 monocyte genes for which basal expression was significantly changed in all 10 subjects after 7 days of ivacaftor. Of these, the majority were increased in expression post ivacaftor, including many genes traditionally associated with enhanced inflammation and immune responses. Pathway analyses confirmed that transcriptional programs were overwhelmingly up-regulated in monocytes after 7 days of ivacaftor, including biological modules associated with immunity, cell cycle, oxidative phosphorylation, and the unfolded protein response. Ivacaftor increased plasma concentrations of CXCL2, a neutrophil chemokine secreted by monocytes and macrophages, and CCL2, a monocyte chemokine.ConclusionsOur results demonstrate that ivacaftor causes acute changes in blood monocyte transcriptional profiles and plasma chemokines, and suggest that increased monocyte inflammatory signals and changes in myeloid cell trafficking may contribute to changes in airway inflammation in people taking CFTR modulators. To our knowledge, this is the first report investigating the transcriptomic response of circulating blood monocytes in CF subjects treated with a CFTR modulator.
| S-EPMC7461946 | biostudies-literature
Project description:The differentiation of pluripotent stem cells has been broadly used in studying the disease mechanism and development process. We previously described a method for differentiating human pluripotent stem cells (hPSCs) into salivary gland epithelial progenitors (SGEPs). Here, to investigate whether the hPSCs-derived SGEPs are capable of modeling the characteristics of cystic fibrosis (CF), a disease impact SG function caused by mutation of cystic fibrosis transmembrane conductance regulator (CFTR) gene, the CFTR knockout hPSCs were differentiated into CF-SGEPs using the same protocol. Firstly, we successfully generated CFTR knockout hPSCs with reduced CFTR protein expression using the CRISPR-Cas9 system. After 16-day of differentiation, the protein expression of CFTR was also decreased in SGEPs generated from CFTR knockout hPSCs. RNA-sequencing shows that multiple genes modulating SG development, function and were down-regulated and positive regulators of inflammation were up-regulated in CF-SGEPs, which was correlated with salivary phenotype in CF patients. These results demonstrated that suppression of CFTR disrupted the differentiation of hPSCs-derived SGEPs, which modeled the SG development of patients with CF. In summary, this study not only provided the proof that the hPSCs-derived SGEPs could serve as manipulatable and easily accessible models to study the SG developmental diseases, but also provided new avenues for the study of the CF mechanism.
2023-12-06 | GSE224547 | GEO
Project description:The purpose of this study was to explore miRNA mediated Transforming Growth Factor (TGF)-β1 regulation of F508del Cystic Fibrosis Transmembrane Conductance regulator (CFTR). To fulfill this goal, miRNA sequencing was done to see miRNA landscape in Cystic Fibrosis Bronchial Epithelial (CFBE) Cells with homozygous WT-CFTR and F508del mutated CFTR in response to TGFβ1 treatment.
2019-03-25 | GSE128765 | GEO
Project description:Cystic fibrosis (CF), caused by mutations to CFTR, leads to severe and progressive lung disease. The most common mutant, ΔF508-CFTR, undergoes proteasomal degradation, depleting its anion channel function. “Proteostasis” pathways, i.e. those relevant to protein processing and trafficking, are altered in cells with ΔF508-CFTR and can be modulated to partially rescue protein function. However, many details regarding proteostasis modulation, and its relevance to CF and ΔF508-CFTR rescue, remain poorly understood. To shed light on this, we re-analyzed public datasets characterizing transcription in CF vs. non-CF epithelia from human and pig airways, and also profiled established temperature, genetic, and chemical interventions that rescue ΔF508-CFTR. Meta-analysis yielded a core disease signature and two core rescue signatures. To interpret these, we compiled proteostasis pathways and an original “CFTR Gene Set Library”. The disease signature revealed differential regulation of mTORC1 signaling, endocytosis, and proteasomal degradation. Overlaying functional genomics data identified candidate mediators of low-temperature rescue, while multiple rescue strategies converged on activation of unfolded protein response pathways. Remarkably, however, C18, an analog of the CFTR corrector compound Lumacaftor, induced minimal transcriptional perturbation despite its rescue activity. This work elucidates the involvement of proteostasis in both disease and rescue perturbations while highlighting that not all CFTR rescue interventions act on transcription.
2020-12-01 | GSE142610 | GEO
Project description:Organotypic culture systems from disease-specific induced pluripotent stem cells (iPSCs) exhibit obvious advantages compared to immortalized cell lines and primary cell cultures but implementation of iPSC-based high throughput (HT) assays is still technically challenging. Here we demonstrate the development and conduction of an organotypic HT Cl-/I- exchange assay using Cystic Fibrosis (CF) disease-specific iPSCs. The introduction of a halide sensitive YFP variant enabled automated quantitative measurement of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) function in iPSC-derived intestinal epithelia. CFTR function was partially rescued by treatment with VX-770 and VX-809, and seamless gene correction of the p.Phe508del mutation resulted in full restoration of CFTR function. The identification of a series of validated primary hits that improve the function of p.Phe508del CFTR from a library of ~ 42.500 chemical compounds demonstrates that the advantages of complex iPSC-derived culture systems for disease modelling can also be utilized for drug screening at a true HT format.
2019-05-11 | GSE129168 | GEO
Project description:Cystic fibrosis (CF) is an inherited, multi-system disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a ubiquitous ion channel important for epithelial hydration. A direct consequence of this dysfunction is impaired mucociliary clearance, chronic airway infection and a persistent neutrophilic inflammatory response that results in progressive loss of lung function, development of respiratory failure and premature death. Partial restoration of CFTR function is now possible for most CF patients through mutation specific CFTR modulators. Ivacaftor monotherapy produces significant clinical improvement in CF patients with the G511D mutation. Dual therapy, combining ivacaftor with lumacaftor or tezacaftor, results in modest clinical improvements in patients homozygous for F508del. More recently, triple therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has led to dramatic improvements in lung function and quality of life in patients homozygous and heterozygous for F508del. Sputum proteomics is a powerful research technique capable of identifying important airway disease mechanisms by interrogating the proteome, an entire set of proteins within biological samples. It has confirmed the central role of neutrophilic immune dysregulation in CF and non-CF bronchiectasis, particularly involving the release of antimicrobial proteins and neutrophil-extracellular traps (NETs), and through impaired anti-inflammatory mechanisms. These processes produce distinct molecular signatures within the sputum proteome that become increasingly abnormal with chronic airway infection and progressive lung disease severity. In CF patients, airway and systemic inflammatory cytokines potentially related to these signatures reduce with the various forms of CFTR modulation. To date, no studies of ETI therapy in CF lung disease have assessed large-scale change in protein expression using untargeted proteomics. We hypothesised that ETI therapy would shift the sputum proteome toward health, potentially normalising airway biology in people with CF. The objectives of this study were to investigate changes in the CF sputum proteome with the introduction of ETI, correlate these with changes in clinical markers of disease severity, and make comparisons with the sputum proteome in healthy controls and in repeat samples from CF patients not suitable for ETI therapy. We also explored which molecular pathways associated with CF lung disease did not change with ETI.
2023-11-14 | PXD041950 | Pride