Recruited monocytes/macrophages drive pulmonary neutrophilic inflammation and irreversible lung tissue remodeling in cystic fibrosis.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA896943 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22142000_1.fastq.gz | Fastqsanger.gz | |||
| SRR22142000_2.fastq.gz | Fastqsanger.gz | |||
| SRR22142001_1.fastq.gz | Fastqsanger.gz | |||
| SRR22142001_2.fastq.gz | Fastqsanger.gz | |||
| SRR22142002_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 64 |
Similar Datasets
Project description:Controlled recruitment of C-C Motif Chemokine Receptor 2 (CCR2)-positive monocytes into lung tissues is a crucial component of the host immune response to infections. Pathogenesis of cystic fibrosis (CF) lung remodeling, which ultimately leads to respiratory failure, is caused by chronic infections and neutrophilic inflammation, but the immune mechanisms are not fully understood. Here, we show that lung explants from CF patients with severe disease contain abundant CCR2-positive classical monocytes in the submucosal tissues of small airways and areas of tissue remodeling. Recapitulating human CF lung remodeling by repeatedly exposing CF mice to lipopolysaccharide (LPS), and by using genetic ablation or pharmacological inhibition of CCR2, we demonstrate that CCR2-dependent accumulation of classical monocytes and monocyte-derived macrophages drive lung neutrophilia, pathogenic Transforming Growth Factor Beta signaling and irreversible lung tissue scarring. Importantly, six weeks after cessation of LPS exposure, the lungs of CF mice still have elevated numbers of pro-inflammatory monocytes with higher expression of neutrophil chemoattractants, thus perpetuating recruitment of neutrophils and lung tissue damage. Lastly, we demonstrate that the increased accumulation of immune cells to inflamed lungs is driven by dysfunctional CF transmembrane conductance regulator (CFTR) expression in CCR2-positive cells. These studies identify uncontrolled recruitment of CCR2-positive cells as a key driver of lung remodeling, and as a novel therapeutic target for patients with CF for which lung hyper-inflammation and tissue damage remain an issue despite recent advances in CFTR-specific therapeutics. Keywords: monocytes; macrophages; neutrophils; chronic lung inflammation; lipopolysaccharide; recruitment; CC-motif chemokine receptor 2; transforming growth factor beta; lung remodeling; cystic fibrosis
2022-12-01 | GSE217102 | GEO
Project description:Persistent neutrophil-dominated lung inflammation contributes to lung damage in cystic fibrosis (CF). However, the mechanisms that drive persistent lung neutrophilia and tissue deterioration in CF are not well characterized. Starting from the observation that, in patients with CF, c-c motif chemokine receptor 2 (CCR2)+ monocytes/macrophages are abundant in the lungs, we investigate the interplay between monocytes/macrophages and neutrophils in perpetuating lung tissue damage in CF. Here we show that CCR2+ monocytes in murine CF lungs drive pathogenic transforming growth factor β (TGF-β) signaling and sustain a pro-inflammatory environment by facilitating neutrophil recruitment. Targeting CCR2 to lower the numbers of monocytes in CF lungs ameliorates neutrophil inflammation and pathogenic TGF-β signaling and prevents lung tissue damage. This study identifies CCR2+ monocytes as a neglected contributor to the pathogenesis of CF lung disease and as a therapeutic target for patients with CF, for whom lung hyperinflammation and tissue damage remain an issue despite recent advances in CF transmembrane conductance regulator (CFTR)-specific therapeutic agents.
| S-EPMC9833830 | biostudies-literature
Project description:Group 3 innate lymphoid cells (ILC3s) have emerged as an important player in the pathogenesis of neutrophilic asthma. However, the regulatory mechanism supporting ILC3 responses in lung remains largely unclear. Here, we demonstrated that stem cell factor (SCF) expression is significantly increased and positively correlated with IL-17A and MPO expression in asthmatic patients. Notably, we identified ILC3 as a major IL-17A-producing responder to SCF in lung. In mice, SCF synergized with IL-1β/IL-23 to enhance pulmonary ILC3 activation and neutrophilic inflammation. Mechanistically, SCF promoted ILC3 proliferation and cytokine production. Transcriptomic analysis revealed that SCF treatment upregulated the genes related to proliferation and Th17 differentiation, associated with increased AKT and STAT3 signaling. In contrast, deficiency of SCF receptor, c-Kit, reduced ILC3 proliferation and IL-17A production, resulting in the amelioration of airway hyperreactivity (AHR) and neutrophilic inflammation in mouse neutrophilic asthma model. Furthermore, genetic deletion of SCF in fibroblasts revealed fibroblasts as the primary source of SCF for ILC3 activation in lung. Moreover, administration of imatinib, a c-Kit inhibitor, alleviated LPS, air pollution or ovalbumin/LPS-induced AHR and neutrophilic inflammation. Our findings elucidated a positive modulatory role of SCF/c-Kit signaling in ILC3 responses during neutrophilic inflammation, offering a potential therapeutic target for neutrophilic asthma.
2025-06-03 | GSE275251 | GEO
Project description:IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we performed single-cell RNA-seq on an acute LPS mouse model of lung inflammation to provide insights into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. We identified neutrophils as a source of IL-36 which provides a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases.
2021-01-25 | GSE159161 | GEO
Project description:Many neutrophilic asthma patients do not respond to current medications, highlighting the need for novel therapeutic targets. Here, we investigated the role of intraflagellar transport (IFT) complex protein IFT20 in neutrophilic asthma. Mice lacking CD4+ T cell-specific IFT20 displayed reduced protease-induced neutrophilic asthma inflammation. Thus, IFT20 may represent a promising therapeutic target for treatment of patients with neutrophilic asthma.
2022-07-31 | GSE179622 | GEO
Project description:Cystic fibrosis (CF) lung disease is dominated by the recruitment of myeloid cells (neutrophils and monocytes) from the blood which fail to clear the lung of colonizing microbes. In prior in vitro studies, we showed that blood neutrophils migrated through the well-differentiated lung epithelium into the CF airway fluid supernatant (ASN) mimic the dysfunction of CF airway neutrophils in vivo, including decreased bactericidal activity despite an increased metabolism. Here, we hypothesized that, in a similar manner to neutrophils, blood monocytes undergo significant adaptations upon recruitment to CFASN. To test this hypothesis, primary human blood monocytes were transmigrated in our in vitro model into the ASN from healthy control (HC) or CF subjects to mimic in vivo recruitment to normal or CF airways, respectively. Surface phenotype, metabolic and bacterial killing activities, and transcriptomic profile by RNA sequencing were quantified post-transmigration. Unlike neutrophils, monocytes were not metabolically activated, nor did they show broad differences in activation and scavenger receptor expression upon recruitment to the CFASN compared to HCASN. However, monocytes recruited to CFASN showed decreased bactericidal activity. RNASeq analysis showed strong effects of transmigration on monocyte RNA profile, with differences between CFASN and HCASN conditions, notably in immune signaling, including lower expression in the former of the antimicrobial factor ISG15, defensin-like chemokine CXCL11, and nitric oxide-producing enzyme NOS3. While monocytes undergo qualitatively different adaptations from those seen in neutrophils upon recruitment to the CF airway microenvironment, their bactericidal activity is also dysregulated, which could explain why they also fail to protect CF airways from infection.
| S-EPMC7959310 | biostudies-literature
Project description:A Lactobacilli-Based Inhaled Live Biotherapeutic Product Attenuates Pulmonary Neutrophilic Inflammation
| PRJNA1132278 | ENA
Project description:The mechanism of neutrophilic and mixed neutrophilic-eosinophilic asthma is poorly understood. We found that extracellular DNA and nucleosomes (Nucs) were elevated in the airways from neutrophilic-eosinophilic asthma patients and correlated with bronchoalveolar lavage neutrophils. Bronchial tissue from neutrophilic-eosinophilic asthma expressed increased DNA sensor-positive cells. Intranasally administered DNA did not induce airway hyperreactivity (AHR) or any pathology but induced AHR and neutrophilic-eosinophilic inflammation when co- administered with the allergen Alternaria (Alt). Nucs alone induced anti-inflammatory/defensive genes whereas the Nuc-Alt combo increased TNFα and innate cytokines. The Alt-Nuc phenotype was abolished in cGas-/- , Alr-/- , Sting-/- , LysMcre:Stingf/f, Il7rcre:Roraf/f and Tnfrsf1b-/- mice. Alt, unexpectedly, played an essential role in the Nuc-induced phenotype. It abrogated Nuc-induction of anti_x0002_inflammatory genes, facilitated Nuc uptake, induced ILC2s, which, in presence of Nucs, produced high levels of TNFα and promoted neutrophilic infiltration. We established a paradigm where allergens inhibit the anti-inflammatory effects of DNA/Nucs and facilitate STING-TNFα-driven neutrophilic-eosinophilic inflammation in asthma.
2025-06-06 | GSE297626 | GEO
Project description:IL-36 Amplifies Neutrophilic Lung Inflammation
| PRJNA667850 | ENA
Project description:Long-term, low dose azithromycin reduces exacerbation frequency in COPD yet the mechanism remains unclear. This study characterises changes to gene expression in patients with neutrophilic COPD in response to long term low dose azithromycin therapy. Patients with neutrophilic COPD (>61% or >162x10^4/mL sputum neutrophils) were randomised to 12 weeks of either azithromycin or placebo treatment. RNA was extracted from sputum and blood collected before (pre) and after (post) treatment.
2018-11-14 | GSE119314 | GEO