Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA391959 | ENA |
REPOSITORIES: ENA
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Project description:Rationale: Chronic sarcoidosis is a complex granulomatous disease with limited treatment options that can progress over time. Understanding the molecular pathways contributing to disease would aid in new therapeutic development. Objectives: To understand if macrophages from non-resolving chronic sarcoidosis patients are predisposed to macrophage aggregation and granuloma formation, and if modulation of the underlying molecular pathways influence sarcoidosis granuloma formation. Methods: Macrophages were cultivated in vitro from isolated peripheral blood CD14+ monocytes and evaluated for spontaneous aggregation. Transcriptomics analyses, phenotypic and drug inhibitory experiments were performed on these monocyte-derived macrophages. Human skin biopsies from sarcoidosis patients and a myeloid Tsc2-specific sarcoidosis mouse model were analyzed for validatory experiments. Measurements and Main Results: Monocyte-derived macrophages from chronic sarcoidosis patients spontaneously formed extensive granulomas in vitro compared to healthy controls. Transcriptomic analyses separated healthy and sarcoidosis macrophages and identified an enrichment in lipid metabolic processes. In vitro patient granulomas, sarcoidosis mouse model granulomas, and those directly analyzed from lesional patient skin expressed an aberrant lipid metabolism profile and contained increased neutral lipids. Conversely, a combination of statins and cholesterol-reducing agents reduced granuloma formation both in vitro and in vivo in a sarcoidosis mouse model. Conclusions: Together, our findings show that altered lipid metabolism in sarcoidosis macrophages is associated with its predisposition to granuloma formation and suggest cholesterol-reducing therapies as a treatment option in patients.
2024-05-22 | GSE250508 | GEO
Project description:Rationale: A well-validated animal model of sarcoidosis can help advance our understanding of the pathobiology of this complex disease. We have developed a multiwall carbon nanotube (MWCNT) based murine model that shows marked histological and inflammatory signal similarities to human sarcoidosis. In this study, we compared the alveolar immune cell transcriptional signatures of our murine model with human sarcoidosis to comprehensively assess overlapping molecular programs. Methods: Total RNA was extracted from alveolar macrophages of 6 MWCNT mice and 6 control mice and hybridized to Illumina Mouse WG-6 v2 microarrays. Transcriptional profiling of alveolar immune cells in 15 sarcoidosis patients and 12 healthy humans was previously performed using Affymetrix Human GeneChip U133A 2.0 microarrays. Rigorous statistical methods were used to identify differentially expressed genes. To better elucidate gene expression pathways, integrated network and gene set enrichment analysis (GSEA) were applied. To confirm differential expression of select network genes, we performed qPCR studies using the ABI Prism 7300 Detection. Results: We identified over 1000 genes that were differentially expressed between the control and the MWCNT mice. Gene Ontology functional analysis showed over-representation of processes primarily involved in immunity and inflammation in MCWNT mice. Applying a more comprehensive pathway analysis using GSEA to both mouse and human samples revealed upregulation of 92 gene sets in MWCNT mice and 142 gene sets in sarcoidosis patients. Commonly activated pathways in both MWCNT mice and sarcoidosis included adaptive immunity, T-cell signaling, IL-12/IL-17 signaling and oxidative phosphorylation. Differences in selective gene set enrichment between MWCNT mice and sarcoidosis patients were also observed, among them IL-27 signaling, NK-mediated cytotoxicity and proteasome pathways. We applied network analysis to differentially expressed genes common between the MWCNT model and human sarcoidosis to identify key drivers of disease and putative therapeutic targets. Conclusions: Our MWCNT murine model has an alveolar macrophage signature that varies significantly from control mice. Application of an unbiased transcriptomic approach revealed substantial functional similarities between a murine MWCNT model and human sarcoidosis particularly with respect to activation of immune-specific pathways.
2017-12-01 | GSE100500 | GEO
Project description:Sarcoidosis is a granulomatous disease of unknown cause. We performed single-cell RNA sequencing to identify the macrophages that comprise sarcoidosis granulomas.
2023-09-25 | GSE234901 | GEO
Project description:Purpose: Using single-cell RNA sequencing to explore the common and unique pathways between progressive (SarcP) and remitting (SarcR) sarcoidosis as well as chronic beryllium disease (CBD) and sarcoidosis, focusing on macrophages and macrophages subpopulations (recruited vs. resident). Methods: We used scRNA-seq to analyze BAL cells from SarcP (N=2), SarcR (N=2), and CBD (N=3) compared to beryllium sensitized non-diseased subjects (BeS; N=2) or healthy control (Con; N=4). The controls were from Mould KJ, et al. Airspace Macrophages and Monocytes Exist in Transcriptionally Distinct Subsets in Healthy Adults. Am J Respir Crit Care Med 2020. We used the R package Seurat to project cells unto Uniform Manifold Approximation and Projection (UMAP) 2D space, identify cell clusters, and detect differentially expressed (DE) genes. Results: We focused our analysis on macrophages (excluding cell clusters going through the cell cycle). We first compared disease groups to healthy control Using False Discovery Rate (FDR) adjusted p<0.05 and absolute log fold change (log FC)>0.25. We identified 191, 242, and 234 DE genes within all macrophages for the comparisons of SarcP vs. Con, SarcR vs. Con, and CBD vs. Con, respectively, with 82 genes common to all three comparisons; 47 out of the 82 genes were common to all comparisons in regards to recruited macrophages. Conclusions: We focused this first single-cell transcriptome study in granulomatous lung disease on macrophages. This study offers investigators cell-specific transcriptional changes (genes and networks/pathways) to consider mechanisms of granulomatous disease and as potential drug targets.
2021-09-27 | GSE184735 | GEO
Project description:Here we have performed qualitative profiling of the membrane-associated proteome of alveolar macrophages in sarcoidosis patients and healthy individuals with the aim to identify specific proteins and pathways involved in sarcoidosis pathology.
2016-12-23 | PXD000752 | Pride
Project description:Cutaneous sarcoidosis skin provides relatively non invasive access to granulomatous sarcoidosis tissue.
2011-10-13 | GSE32887 | GEO
Project description:Pulmonary sarcoidosis is an inflammatory disease characterized by granuloma formation and heterogeneous clinical outcome. TNF is a proinflammatory cytokine contributing to granuloma formation and high levels of TNF have been shown to associate with progressive disease. Mononuclear phagocytes (MNPs) are potent producers of TNF and highly responsive to inflammation. In sarcoidosis, alveolar macrophages (AMs) have been well studied. However, MNPs also include monocytes/monocyte-derived cells and dendritic cells (DCs) that despite their central role in inflammation are poorly studied in sarcoidosis. We performed in-depth phenotypic, functional and transcriptomic analysis of MNPs subsets from blood and bronchoalveolar lavage (BAL) fluid from 108 sarcoidosis patients and 30 healthy controls.
2021-05-19 | GSE174659 | GEO
Project description:Cardiac involvement is an important determinant of mortality amongst sarcoidosis patients. While granulomatous inflammation is a hallmark finding in cardiac sarcoidosis, the precise immune cell populations that comprise the granuloma remain unresolved. Furthermore, it is unclear how the cellular and transcriptomic landscape of cardiac sarcoidosis differs from other inflammatory heart diseases. We leveraged spatial transcriptomics (GeoMx DSP) and single nucleus RNA sequencing (snRNAseq) to elucidate the cellular and transcriptional landscape of cardiac sarcoidosis. Using GeoMX DSP technology, we compared the transcriptomal profile of CD68+ rich immune cell infiltrates in human cardiac sarcoidosis, giant cell myocarditis, and lymphocytic myocarditis. We performed snRNAseq of human cardiac sarcoidosis to identify immune cell types and examined their transcriptomic landscape and regulation. Using multi-channel immunofluorescence staining, we validated immune cell populations identified by snRNAseq, determined their spatial relationship, and devised an immunostaining approach to distinguish cardiac sarcoidosis from other inflammatory heart diseases. Despite overlapping histological features, spatial transcriptomics identified transcriptional signatures and associated pathways that robustly differentiated cardiac sarcoidosis from giant cell myocarditis and lymphocytic myocarditis. snRNAseq revealed the presence of diverse populations of myeloid cells in cardiac sarcoidosis with distinct molecular features. We identified GPNMB as a novel marker of multinucleated giant cells and predicted that the MITF family of transcription factors regulated this cell type. We also detected additional macrophage populations in cardiac sarcoidosis including HLA-DR+ macrophages, SYTL3+ macrophages and CD163+ resident macrophages. HLA-DR+ macrophages were found immediately adjacent to GPMMB+ giant cells, a distinct feature compared with other inflammatory cardiac diseases. SYTL3+ macrophages were located scattered throughout the granuloma and CD163+ macrophages, CD1c+ dendritic cells, non-classical monocytes, and T-cells were located at the periphery and outside of the granuloma. Finally, we demonstrate mTOR pathway activation is associated with proliferation and is selectively found in HLA-DR+ and SYLT3+ macrophages. In this study, we identified diverse populations of immune cells with distinct molecular signatures that comprise the sarcoid granuloma. These findings provide new insights into the pathology of cardiac sarcoidosis and highlight opportunities to improve diagnostic testing.
2022-07-01 | GSE205734 | GEO
Project description:Cutaneous sarcoidosis skin provides relatively non invasive access to granulomatous sarcoidosis tissue. Twenty participants were enrolled: 15 with active CS and 5 healthy volunteers. Microarray analyses comparing non-LS and healthy volunteer skin with LS showed several thousand genes differentially expressed
2011-10-12 | E-GEOD-32887 | biostudies-arrayexpress
Project description:The goal of this study was to investigate and correlate differential methylation and expression in cells from the target organ in non-infectious granulomatous lung diseases, specifically sarcoidosis and chronic beryllium disease (CBD). To that end, cells were collected from patients via bronchoalveolar lavage (BAL), and extracted nucleic acids were hybridized to genome-wide arrays. We conclude that there are many genes that are both differentially methylated and expressed in the BAL fluid of patients with granulomatous lung disease. We identified 2,726 differentially methylated CpGs mapping to 1,944 unique genes when comparing CBD patients to beryllium-sensitized (BeS) individuals without disease. 69% of these genes were also differentially expressed in CBD. Sarcoidosis patients exhibited directional consistency at many loci, but genome-wide significance was not achieved, likely due to heterogeneity in the patient population.
2018-12-05 | GSE110777 | GEO