Activation of the pentose phosphate pathway in macrophages is crucial for granuloma formation in sarcoidosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE234901 | GEO | 2023/09/25
REPOSITORIES: GEO
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Project description:Sarcoidosis is a disease of unknown etiology in which granulomas form throughout the body and is typically treated with glucocorticoids, but there are no approved steroid-sparing alternatives. Here, we investigated the mechanism of granuloma formation using single-cell RNA-Seq in sarcoidosis patients. We observed that the percentages of triggering receptor expressed on myeloid cells 2-positive (TREM2-positive) macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, diagnostic makers of sarcoidosis, were increased in cutaneous sarcoidosis granulomas. Macrophages in the sarcoidosis lesion were hypermetabolic, especially in the pentose phosphate pathway (PPP). Expression of the PPP enzymes, such as fructose-1,6-bisphosphatase 1 (FBP1), was elevated in both systemic granuloma lesions and serum of sarcoidosis patients. Granuloma formation was attenuated by the PPP inhibitors in in vitro giant cell and in vivo murine granuloma models. These results suggest that the PPP may be a promising target for developing therapeutics for sarcoidosis.
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Project description:Activation of the pentose phosphate pathway in macrophages is crucial for granuloma formation in sarcoidosis
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Project description:Gene expression analysis of primary CSF1-deprived bone marrow-derived macrophages (BMDM) of Tsc2fl/fl LysM+/+ and TSC2fl/fl LysM+/cre mice Maintenance of tissue homeostasis requires a tight control of the in situ-proliferative capacity of tissue-resident macrophages. Here we show that specific deletion of Tsc2 in myeloid cells breaks quiescence and strongly induces macrophage proliferation and hypertrophy leading to granuloma formation in vivo in an mTORC1-dependent manner. Intriguingly, the growth factor CSF1 induces expression of cyclin-dependent kinase 4 (CDK4) via TSC2-mTORC1 to stimulate cell proliferation, while simultaneously NF-κB signaling and apoptosis are inhibited. Tsc2-deficient macrophages show constitutive CDK4 expression and enhanced M2-like polarization that is supported by a metabolic reprogramming towards increased glycolysis and mitochondrial metabolism. Strikingly, mTORC1 activation and macrophage proliferation are identified as a hallmark of the human granulomatous disease sarcoidosis and correlate with a clinically progressive disease outcome. In conclusion, TSC2-mTORC1 integrates macrophage quiescence, polarization, and metabolism to prevent granulomatous disease. Fundamentally, we show that the macrophage cell cycle is controlled by a growth factor-induced expression of CDK4.
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Project description:Cutaneous sarcoidosis skin provides relatively non invasive access to granulomatous sarcoidosis tissue.
2011-10-13 | GSE32887 | GEO
Project description:Rationale: Despite the availability of multi-“omics” strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures. Objective: To facilitate the development sarcoidosis genomic biomarkers by gene expression profiling of sarcoidosis granulomas in lung and lymph node tissues (most commonly affected organs) and comparison to infectious granulomas (coccidiodomycosis and tuberculosis).
2020-12-09 | GSE157671 | 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.
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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
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Project description:Sarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ~20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis). Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated) sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis. We utilized genome-wide peripheral blood gene expression analysis to identify a gene signature distinguishing sarcoidosis from healthy controls, which also served as a molecular signature for complicated sarcoidosis.
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Project description:The severity of schistosome egg-induced hepatic granulomatous pathology depends markedly on the nature of the mammalian host immune response. The local cellular and molecular mechanisms that co-ordinate hepatic granuloma formation during schistosome infection are still poorly understood. We used a combination of laser microdissection microscopy and microarray analysis to further our understanding of fibrogenesis and granuloma formation in C57BL/6 mice infected with Schistosoma japonicum. We compared hepatic gene expression profiles in histologically distinct zones both within, and directly proximal to, granulomas during the course of their development.
2012-11-01 | GSE41941 | GEO
Project description:Sarcoidosis is a multiorgan inflammatory disease that is characterized by tissue granulomas and remains so challenging for clinicians to diagnose that it has been called “the great imitator”. Here, by performing single-cell sequencing and spatial transcriptomics on skin granulomas from sarcoid and non-sarcoid patients, we discovered increased recruitment of innate lymphoid cells in granulomas. Sarcoid-associated cells exhibited increased cell migration compared to healthy individuals. Importantly, granuloma formation was attenuated in mice genetically lacking these cells or treated with a pharmacologic inhibitor.
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