The influence of CLEC5A on early macrophage-mediated inflammation in COPD progression.
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ABSTRACT:
PROVIDER: PRJNA1074671 | ENA |
REPOSITORIES: ENA
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Project description:Methods: This study analyzed lung tissue sequencing data from early-stage COPD patients (GSE47460) and smoke-exposed mice. We employed Weighted Gene Co-Expression Network Analysis (WGCNA) and machine learning to identify potential pathogenic genes. Further analyses included single-cell sequencing from mice and COPD patients to identify gene expression in specific cell subgroups. Cell-chat and pseudo-temporal analyses were conducted, with findings validated in smoke-exposed mice. Additionally, Mendelian randomization (MR) was utilized to verify the relationship between candidate genes and lung function/COPD. Lastly, functional validation was performed in vitro in cell cultures. Results: "Machine learning analysis of 30 differentially expressed genes pinpointed 8 key genes, with CLEC5A identified as a potential pathogenic factor in early COPD. Bioinformatics suggested CLEC5A's role in macrophage-mediated inflammation in COPD. Two-sample Mendelian randomization linked CLEC5A SNPs with FEV1, FEV1/FVC, and emphysema/chronic bronchitis. In vitro, CLEC5A knockdown reduced inflammatory markers in macrophages. Conclusion: Our study identifies CLEC5A as a pivotal gene in early-stage COPD, contributing to its pathogenesis through pro-inflammatory mechanisms. This discovery offers insights for early diagnosis and treatment strategies in COPD, highlighting CLEC5A as a target for further research.
2024-07-21 | GSE255319 | GEO
Project description:Rationale: COPD (Chronic Obstructive Pulmonary Disease) is a disease characterized by persistent airway inflammation and disordered macrophage function. The extent to which alterations in macrophage bioenergetics contribute to impaired antioxidant responses and disease pathogenesis has yet to be fully delineated. Objectives: Through the study of COPD alveolar (AM) and peripheral monocyte-derived (MDM) macrophages, we sought to establish if intrinsic defects in core metabolic processes drive macrophage dysfunction and redox imbalance. Methods: AM and MDM from COPD and healthy donors underwent functional, metabolic and transcriptional profiling. Results: We observe that AM and MDM from COPD donors display a critical depletion in glycolytic and mitochondrial respiration derived energy reserves and an over reliance on glycolysis as a source for ATP, resulting in reduced energy status. Defects in oxidative metabolism extend to an impaired redox balance associated with defective expression of the NADPH generating enzyme, malic enzyme 1, a known target of the anti-oxidant transcription factor NRF2. Consequently, selective activation of NRF2 resets the COPD transcriptome, resulting in increased generation of TCA cycle intermediaries, improved energetic status, favorable redox balance and a recovery of macrophage function. Conclusion: In COPD an inherent loss of metabolic plasticity leads to metabolic exhaustion and reduced redox capacity which can be rescued by activation of the NRF2 pathway. Targeting these defects, via NRF2 augmentation, may therefore present an attractive therapeutic strategy for the treatment of the aberrant airway inflammation described in COPD.
2023-04-02 | PXD040504 | Pride
Project description:Chronic obstructive pulmonary disease (COPD) is characterized by persistent and amplified inflammation to cigarette smoke in vulnerable subjects. The genetic risk of persistent inflammation is poorly understood. A mouse model targeting hedgehog interacting protein (HHIP)(Hhip+--), a genetic risk factor for COPD, displays progressive, persistent inflammation resembling human cases, providing a valuable model to study the contribution of the genetic risk factor HHIP to inflammation in COPD. By single cell RNA sequencing of Hhip+-- lungs at different disease stages, we identified induction of IFN-gamma in activated CD8+T cells possibly driving the inflammatory phenotype in Hhip+-- lungs. Hhip expression was restricted to lung fibroblasts, which interaction with CD8+T cells were mediated by increased levels of IL-18 from Hhip+-- fibroblasts. Our finding provides insight into how a common genetic variation contributes to the amplified lymphocytic inflammation in COPD.
2021-08-01 | GSE149843 | GEO
Project description:Background: When exposed to specific stimuli, macrophages exhibit distinct activation programs, M1 and M2 polarization, that define macrophage function as inflammatory/immune effectors or anti-inflammatory/tissue remodeling cells, respectively. Due to their position on the lung epithelial surface, alveolar macrophages (AM) directly interact with environmental stimuli such as cigarette smoke, the major risk factor for the development of chronic obstructive pulmonary disease (COPD). Based on the current paradigm that, in response to smoking, AM contribute to both inflammatory and tissue remodeling processes in the lung relevant to the pathogenesis of COPD, we hypothesized that chronic exposure to cigarette smoking activates both the M1 and M2 polarization programs in AM. Methods and Findings: To assess this hypothesis, global transcriptional profiling with TaqMan confirmation and flow cytometry analysis was carried out on AM obtained by bronchoalveolar lavage of 24 healthy nonsmokers, 34 healthy smokers and 12 smokers with COPD to assess the expression of 41 M1 genes and 32 M2 genes in each group. Contrary to our expectations, while there was up-regulation of some genes typical for M2-related phenotypes, AM of healthy smokers exhibited substantial suppression of M1-related inflammatory/immune genes. These M1- and M2-related changes progressed with the development of smoking-induced lung disease, with AM of smokers with COPD exhibiting further down-regulation of M1-related genes accompanied with further up-regulation of some M2-related genes. Conclusion: The data demonstrates that the modifications of the AM transcriptome associated with smoking result in a unique phenotype characterized by reprogramming of AM towards M1-deactivated partially M2-polarized macrophages and suggests that, while AM likely contribute to smoking-induced tissue remodeling, the role of AM in the early pathogenesis of smoking-induced COPD in humans is not inflammatory. This concept is a departure from the conventional concept that AM-mediated inflammation participates in the early derangements of the lung induced by smoking, and suggests a novel paradigm for conceptualizing COPD and developing new approaches to prevent the development of smoking-induced lung disease. Comparison of gene expression in alveolar macrophages of normal non-smokers and normal smokers and smokers with COPD
2009-08-09 | E-GEOD-13896 | biostudies-arrayexpress
Project description:The role of HHIP in COPD lymphocytic inflammation
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Project description:Background: When exposed to specific stimuli, macrophages exhibit distinct activation programs, M1 and M2 polarization, that define macrophage function as inflammatory/immune effectors or anti-inflammatory/tissue remodeling cells, respectively. Due to their position on the lung epithelial surface, alveolar macrophages (AM) directly interact with environmental stimuli such as cigarette smoke, the major risk factor for the development of chronic obstructive pulmonary disease (COPD). Based on the current paradigm that, in response to smoking, AM contribute to both inflammatory and tissue remodeling processes in the lung relevant to the pathogenesis of COPD, we hypothesized that chronic exposure to cigarette smoking activates both the M1 and M2 polarization programs in AM. Methods and Findings: To assess this hypothesis, global transcriptional profiling with TaqMan confirmation and flow cytometry analysis was carried out on AM obtained by bronchoalveolar lavage of 24 healthy nonsmokers, 34 healthy smokers and 12 smokers with COPD to assess the expression of 41 M1 genes and 32 M2 genes in each group. Contrary to our expectations, while there was up-regulation of some genes typical for M2-related phenotypes, AM of healthy smokers exhibited substantial suppression of M1-related inflammatory/immune genes. These M1- and M2-related changes progressed with the development of smoking-induced lung disease, with AM of smokers with COPD exhibiting further down-regulation of M1-related genes accompanied with further up-regulation of some M2-related genes. Conclusion: The data demonstrates that the modifications of the AM transcriptome associated with smoking result in a unique phenotype characterized by reprogramming of AM towards M1-deactivated partially M2-polarized macrophages and suggests that, while AM likely contribute to smoking-induced tissue remodeling, the role of AM in the early pathogenesis of smoking-induced COPD in humans is not inflammatory. This concept is a departure from the conventional concept that AM-mediated inflammation participates in the early derangements of the lung induced by smoking, and suggests a novel paradigm for conceptualizing COPD and developing new approaches to prevent the development of smoking-induced lung disease.
2009-08-10 | GSE13896 | GEO
Project description:Chronic obstructive pulmonary disease (COPD) is a worldwide public health challenge because of its high prevalence and related disability and mortality; however, the pathogenesis of COPD remains unknown. The aim of this study was to reveal the critical proteins involved in the pathogenesis of COPD. This study used high-resolution liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), in combination with quantitative 6-plex tandem mass tag labeling, to profile protein changes in lung tissues from patients with COPD and healthy donors. Western blot analyses were used to validate the proteomic data. A total of 4976 proteins were identified and analyzed. One-hundred and seventy-three proteins were found significantly changed, with 118 proteins downregulated and 55 proteins upregulated. Gene ontology analysis and protein-protein interaction networks demonstrated that the changed proteins, especially down-regulated proteins, were involved in platelet and macrophage activation. Our results indicated that abnormal platelet activation caused by down-regulation of GP6, PF4, and THBS1 contributes to the hemostasis disorders, while dysfunction of alveolar macrophages in efferocytosis, as a result of down-regulation of CD163 and MARCO, caused the failure of resolution of inflammation, and thus cause COPD.
2020-01-17 | PXD017158 |
Project description:Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease leading to irreversible airflow limitation and is characterized by chronic pulmonary inflammation，obstructive bronchiolitis and emphysema. Etiologically, COPD is mediated by toxic gases and particles, e.g. cigarette smoke, while the pathogenesis of the disease is largely unknown. Several lines of evidence indicate a link between COPD and autoimmunity but comprehensive studies are lacking. By using a protein microarray assaying more than 19,000 human proteins we determined in this study the autoantibody profiles of COPD and non-COPD smokers.
2019-06-21 | GSE133096 | GEO
Project description:Abstract: Chronic obstructive pulmonary disease (COPD) is a progressive lung disease for which there is no cure. Accumulating research results suggest a role for extracellular vesicles (EVs) in the pathogenesis of COPD. This study aimed to uncover the involvement of EVs and their molecular cargo in the progression of COPD by identification of EV-associated protein and microRNA (miRNA) profiles. We isolated EVs from bronchial alveolar lavage fluid (BALF) of 18 patients with COPD and 11 healthy controls by size exclusion chromatography. EV isolates were characterized by Nnanoparticle tracking analysis and protein content. Proteomic analysis revealed higher abundance of 284 proteins (log2FC > 1) and lower abun-dance of 3 proteins (log2FC <-1) in EVs derived from patients with COPD. Ingenuity pathway analysis showed that proteins enriched in COPD-associated EVs trigger inflammatory responses including neutrophil degranulation. Variances in surface receptors and ligands associated with COPD EVs suggested preferential interaction with alveolar cells. Small RNAseq analysis iden-tified higher abundance of ten miRNAs and lower abundance of one in EVs from COPD versus controls (Basemean >100, FDR<0.05). Our data indicate that the molecular composition of EVs in BALF of patients with COPD is altered compared to healthy control EVs. Several components in COPD EVs were identified that may perpetuate inflammation and alveolar tissue destruction.
2024-06-23 | PXD049998 | Pride
Project description:Characterization of Macrophage-Tropic HIV Infection of Central Nervous System Cells and the Influence of Inflammation
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