Dynamically Upregulated Mast Cell CPA3 Patterns in lung disease
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ABSTRACT:
PROVIDER: PRJNA832973 | ENA |
REPOSITORIES: ENA
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Project description:The mast cell-specific metalloprotease CPA3 has been given important roles in lung tissue homeostasis and disease pathogenesis. However, the dynamics and spatial distribution of mast cells CPA3 expression in lung diseases remains unknown. Methods: Using a histology-based approach for spatial and quantitative simultaneous decoding of mRNA and protein expression at a single cell level, this study investigates the dynamics of CPA3 expression across mast cells residing in lungs from healthy controls and patients with severe chronic obstructive pulmonary disease (COPD) or idiopathic lung fibrosis (IPF). Results: Mast cells in COPD lungs had increased CPA3 mRNA (bronchioles p<0.001, pulmonary vessels p< 0.01, alveolar parenchyma p< 0.01) compared to controls, while granule stored CPA3 protein was unaltered. IPF lungs had a significant upregulation of both CPA3 mRNA (p<0.001) and protein (p<0.05) in the fibrotic alveolar tissue. IPF was also characterized by highest density of distal lung mast cells. As an indication of disease relevant increased CPA3 turnover, spatial expression maps revealed altered mast cell mRNA/protein quotients in lung areas subjected to disease-relevant histopathological alterations. Single cell RNA sequencing of bronchial mast cells confirmed CPA3 as a top expressed gene with potential links to both inflammatory and protective markers. Conclusion: This study shows that lung tissue mast cell populations in COPD and IPF-affected lungs have spatially complex and markedly up-regulated CPA3 expression profiles that correlates with sites of structural pathologies. Given the proposed roles of CPA3 in tissue homeostasis, remodeling and inflammation, these alterations are likely to have clinical consequences.
2022-07-28 | GSE201772 | GEO
Project description:BackgroundThe mast cell-specific metalloprotease CPA3 has been given important roles in lung tissue homeostasis and disease pathogenesis. However, the dynamics and spatial distribution of mast cell CPA3 expression in lung diseases remain unknown.MethodsUsing a histology-based approach for quantitative spatial decoding of mRNA and protein single cell, this study investigates the dynamics of CPA3 expression across mast cells residing in lungs from control subjects and patients with severe chronic obstructive pulmonary disease (COPD) or idiopathic lung fibrosis (IPF).ResultsMast cells in COPD lungs had an anatomically widespread increase of CPA3 mRNA (bronchioles p < 0.001, pulmonary vessels p < 0.01, and alveolar parenchyma p < 0.01) compared to controls, while granule-stored CPA3 protein was unaltered. IPF lungs had a significant upregulation of both mast cell density, CPA3 mRNA (p < 0.001) and protein (p < 0.05), in the fibrotic alveolar tissue. Spatial expression maps revealed altered mast cell mRNA/protein quotients in lung areas subjected to disease-relevant histopathological alterations. Elevated CPA3 mRNA also correlated to lung tissue eosinophils, CD3 T cells, and declined lung function. Single-cell RNA sequencing of bronchial mast cells confirmed CPA3 as a top expressed gene with potential links to both inflammatory and protective markers.ConclusionThis study shows that lung tissue mast cell populations in COPD and IPF lungs have spatially complex and markedly upregulated CPA3 expression profiles that correlate with immunopathological alterations and lung function. Given the proposed roles of CPA3 in tissue homeostasis, remodeling, and inflammation, these alterations are likely to have clinical consequences.
| S-EPMC9378779 | biostudies-literature
Project description:Left heart disease (LHD) frequently causes lung vascular remodelling and pulmonary hypertension (PH). Yet, pharmacological treatment for PH in LHD is lacking and its pathophysiological basis remains obscure. We aimed to identify candidate mechanisms of PH in LHD and to test their relevance and therapeutic potential. In rats, LHD was induced by supracoronary aortic banding. Whole genome microarray analyses were performed, candidate genes were confirmed by RT-PCR and Western blots and functional relevance was tested in vivo by genetic and pharmacological strategies. In lungs of LHD rats, mast cell activation was the most prominently upregulated gene ontology cluster. Mast cell gene upregulation was confirmed at RNA and protein levels and remodelled vessels showed perivascular mast cell accumulations. In LHD rats treated with the mast cell stabiliser ketotifen, or in mast cell deficient Ws/Ws rats, PH and vascular remodelling were largely attenuated. Both strategies also reduced PH and vascular remodelling in monocrotaline-induced pulmonary arterial hypertension, suggesting that the role of mast cells extends to noncardiogenic PH. In PH of different aetiologies, mast cells accumulate around pulmonary blood vessels and contribute to vascular remodelling and PH. Mast cells and mast cell-derived mediators may present promising targets for the treatment of PH. Whole rat genome microarray analyses were performed in lung homogenates of three rats with established PH following supracoronary aortic banding and in three sham-operated controls. Out of a total of 28,000 analysed genes, differential expression defined as 2-fold change with p<0.05 was evident for 120 genes. Of these, 76 were upregulated and 44 downregulated in aortic banding compared with control lungs gene. Enrichment analysis revealed regulation of mast cell specific genes - 13 out of 20 genes were significantly upregulated in aortic banding compared with control lungs. To test for a putative functional role of mast cells in lung vascular remodelling and PH in LHD, we applied a pharmacological approach by treatment of aortic banding rats with the mast cell stabiliser ketotifen. Microarray analysis then compared rats that were treated with untreated. In brief, congestive heart failure (CHF) was induced in juvenile rats by supracoronary aortic banding and rats were analyzed 9 weeks thereafter when they had established left heart failure with preserved ejection fraction and secondary pulmonary hypertension. Three heart failure rats were untreated, and 3 received the mast cell stabilizer ketotifen (1 mg/kg-1 bodyweight/day-1) with the drinking water. Sham rats underwent the same surgical procedure but without placement of a clip on the supracoronary aorta. Microarray analyses: Lungs from banded and control rats were excised and total RNA was extracted (Stratagene Absolutely RNA Miniprep Kit; Stratagene, La Jolla, USA). Three µg total RNA from three control and three banded rats each were processed according to the One-Cycle Target Labeling protocol (GeneChip Expression Analysis, Affymetrix, Santa Clara, USA). Before and after amplifications, the total RNA/complementary RNA concentrations were checked with NanoDrop ND-1000 (Thermo Scientific, Wilmington, USA) and quality was controlled (Experion electrophoresis station, BioRad; Hercules, USA). Samples were hybridized to GeneChip® Rat Genome 230 2.0 arrays (Affymetrix; Santa Clara, USA) containing 31,000 probe sets covering 28,000 rat genes.
2016-07-22 | E-GEOD-84704 | biostudies-arrayexpress
Project description:Left heart disease (LHD) frequently causes lung vascular remodelling and pulmonary hypertension (PH). Yet, pharmacological treatment for PH in LHD is lacking and its pathophysiological basis remains obscure. We aimed to identify candidate mechanisms of PH in LHD and to test their relevance and therapeutic potential. In rats, LHD was induced by supracoronary aortic banding. Whole genome microarray analyses were performed, candidate genes were confirmed by RT-PCR and Western blots and functional relevance was tested in vivo by genetic and pharmacological strategies. In lungs of LHD rats, mast cell activation was the most prominently upregulated gene ontology cluster. Mast cell gene upregulation was confirmed at RNA and protein levels and remodelled vessels showed perivascular mast cell accumulations. In LHD rats treated with the mast cell stabiliser ketotifen, or in mast cell deficient Ws/Ws rats, PH and vascular remodelling were largely attenuated. Both strategies also reduced PH and vascular remodelling in monocrotaline-induced pulmonary arterial hypertension, suggesting that the role of mast cells extends to noncardiogenic PH. In PH of different aetiologies, mast cells accumulate around pulmonary blood vessels and contribute to vascular remodelling and PH. Mast cells and mast cell-derived mediators may present promising targets for the treatment of PH. Whole rat genome microarray analyses were performed in lung homogenates of three rats with established PH following supracoronary aortic banding and in three sham-operated controls. Out of a total of 28,000 analysed genes, differential expression defined as 2-fold change with p<0.05 was evident for 120 genes. Of these, 76 were upregulated and 44 downregulated in aortic banding compared with control lungs gene. Enrichment analysis revealed regulation of mast cell specific genes - 13 out of 20 genes were significantly upregulated in aortic banding compared with control lungs. To test for a putative functional role of mast cells in lung vascular remodelling and PH in LHD, we applied a pharmacological approach by treatment of aortic banding rats with the mast cell stabiliser ketotifen. Microarray analysis then compared rats that were treated with untreated.
2016-07-22 | GSE84704 | GEO
Project description:GeneChip Data of human lung mast cells and tonsillar mast cells Keywords: other
2004-10-20 | GSE1848 | GEO
Project description:We are interested in comparing expression patterns of hematopoletic stem cells, mast cell precursors and mature mast cells. Our group recently reported that murine mast cells express CD34, Sca-1 and c-kit. Microarray analysis may uncover other novel surface antigens useful in separating mast cells from stem cells. Experiment Overall Design: this experiment include 2 samples and 12 replicates
2008-06-12 | E-GEOD-3776 | biostudies-arrayexpress
Project description:We are interested in comparing expression patterns of hematopoletic stem cells, mast cell precursors and mature mast cells. Our group recently reported that murine mast cells express CD34, Sca-1 and c-kit. Microarray analysis may uncover other novel surface antigens useful in separating mast cells from stem cells. Keywords: other
2005-12-09 | GSE3776 | GEO
Project description:GeneChip Data of human lung mast cells and tonsillar mast cells
2008-06-11 | E-GEOD-1848 | biostudies-arrayexpress
Project description:Mast cells are phenotypically and functionally highly heterogeneous, and their state is possibly controlled by their local microenvironment. Therefore, concrete analyses are needed to understand whether mast cells act as powerful motivators or dispensable bystanders in specific diseases. Here, we evaluated the correlation between synovial mast cells and rheumatoid arthritis (RA) disease severity, and the efficacy of therapeutic interventions against mast cells. We showed that degranulation of mast cells in inflammatory synovial tissues of RA patients was induced via MAS-related G protein-coupled receptor X2 (MRGPRX2), and the expression of MHC class II (MHC II) and costimulatory molecules on mast cells were upregulated. These unique signaling response led to mast cell activation and promoted T cell responses, resulting in the progression of RA. Collagen-induced arthritis mouse models treated with a combination of anti-IL-17A and cromolyn sodium, a mast cell membrane stabilizer, showed significantly reduced clinical severity and decreased bone erosion. The findings of the present study suggest that synovial microenvironment-influenced mast cells contribute to RA and may provide a novel mast cell-targeting therapy for RA.
2024-01-07 | PXD038584 | Pride
Project description:The regulation of soluble N ethylmaleimide sensitive factor attachment receptor (SNARE) mediated membrane fusion by upstream signaling events is poorly understood. Here we show that the SNARE binding protein tomosyn-1 negatively regulates type I IgE Fc receptor (FcRI) induced degranulation of mast cells. After FcRI stimulation, tomosyn-1 (also STXBP5) was phosphorylated on serine and threonine residues and dissociated from the SNARE protein syntaxin 4 (STX4), followed by association with syntaxin 3 (STX3). Protein kinase A (PKA) and protein kinase C (PKC) prevented these activities. We identified PKC as the major kinase required for tomosyn-1 threonine phosphorylation and for the regulation of the interaction with STXs. Incubation with high IgE concentrations induced tomosyn-1 expression in cultured mast cells. In basophils from allergic patients with normal total IgE serum titers tomosyn-1 expression was lower than in patients with high IgE titers who expressed tomosyn-1 to the same extent as non-allergic subjects. Our findings identified tomosyn-1 as a negative regulator of mast cell degranulation that required PKC to switch its interaction with STX partners during fusion. The IgE-mediated upregulation of tomosyn-1 in allergic patients may represent a counter-regulatory mechanism to limit disease development.
2018-07-04 | PXD010047 | Pride