Monocytes in sarcoidosis are potent tumour necrosis factor producers and predict disease outcome

Lepzien, Rico; Liu, Sang; Czarnewski, Paulo; Nie, Man; Österberg, Björn; Baharom, Faezzah; Pourazar, Jamshid; Rankin, Gregory; Eklúnd, Anders; Bottai, Matteo; Kullberg, Susanna; Blomberg, Anders; Grünewald, Johan; Smed‐Sörensen, Anna

doi:10.1183/13993003.03468-2020

Cited by 31 publications

(42 citation statements)

References 48 publications

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“…In addition, previous studies reported that immune cells constituting recurrent sarcoidosis granulomas in lung transplant allografts originated from the recipient monocyte-macrophage lineage ( 19 , 20 ). Finally, the inflammatory phenotype of MD-macrophages in pulmonary sarcoidosis and their propensity to produce TNFα has been recently highlighted ( 11 ), supporting the role of these cells in sarcoidosis pathogenesis. However, the fact that experiments were almost exclusively performed in MD-macrophages constitutes a limitation of the present study.…”

Section: Discussionmentioning

confidence: 92%

Hypoxia Promotes a Mixed Inflammatory-Fibrotic Macrophages Phenotype in Active Sarcoidosis

et al. 2021

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BackgroundMacrophages are pivotal cells in sarcoidosis. Monocytes-derived (MD) macrophages have recently been demonstrated to play a major role especially in pulmonary sarcoidosis. From inflammatory tissues to granulomas, they may be exposed to low oxygen tension environments. As hypoxia impact on sarcoidosis immune cells has never been addressed, we designed the present study to investigate MD-macrophages from sarcoidosis patients in this context. We hypothesized that hypoxia may induce functional changes on MD-macrophages which could have a potential impact on the course of sarcoidosis.MethodsWe studied MD-macrophages, from high active sarcoidosis (AS) (n=26), low active or inactive sarcoidosis (IS) (n=24) and healthy controls (n=34) exposed 24 hours to normoxia (21% O2) or hypoxia (1.5% O2). Different macrophage functions were explored: hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-kappa B (NF-κB) activation, cytokines secretion, phagocytosis, CD80/CD86/HLA-DR expression, profibrotic response.ResultsWe observed that hypoxia, with a significantly more pronounced effect in AS compared with controls and IS, increased the HIF-1α trans-activity, promoted a proinflammatory response (TNFα, IL1ß) without activating NF-κB pathway and a profibrotic response (TGFß1, PDGF-BB) with PAI-1 secretion associated with human lung fibroblast migration inhibition. These results were confirmed by immunodetection of HIF-1α and PAI-1 in granulomas observed in pulmonary biopsies from patients with sarcoidosis. Hypoxia also decreased the expression of CD80/CD86 and HLA-DR on MD-macrophages in the three groups while it did not impair phagocytosis and the expression of CD36 expression on cells in AS and IS at variance with controls.ConclusionsHypoxia had a significant impact on MD-macrophages from sarcoidosis patients, with the strongest effect seen in patients with high active disease. Therefore, hypoxia could play a significant role in sarcoidosis pathogenesis by increasing the macrophage proinflammatory response, maintaining phagocytosis and reducing antigen presentation, leading to a deficient T cell response. In addition, hypoxia could favor fibrosis by promoting profibrotic cytokines response and by sequestering fibroblasts in the vicinity of granulomas.

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Section: Discussionmentioning

confidence: 92%

Hypoxia Promotes a Mixed Inflammatory-Fibrotic Macrophages Phenotype in Active Sarcoidosis

et al. 2021

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“…The subset distribution differed mostly based on the sampling site as described before. 9,17,20 Analyzing the transcriptome of blood and BAL cells from sarcoidosis patients has often been performed on bulk cells, thereby masking the gene expression by less frequent immune cell subsets. 20,34 Using RNA sequencing, we showed significant differences in genes expression between DCs, monocytes, and monocyte-derived cells from blood and BAL of sarcoidosis patients.…”

Section: Discussionmentioning

confidence: 99%

“…1D), as previously reported. 9,20 Next, DCs, monocytes, and monocyte-derived cells were FACS-sorted and postsorting purity of cells was confirmed to be >95% for each patient and exemplified for 1 patient with May-Grünwald-Giemsa staining (Fig. 1E).…”

Section: Dcs From Sarcoidosis Patients Display a Gene Expression Profile Suggestive Of Superior Antigen Presentation And T Cell Activatiomentioning

confidence: 92%

“…To investigate the differences in T cell activating pathways across monocyte and DC subsets, we made use of our previously published RNA sequencing data, now available as a public dataset GSE174659. 9 In this dataset, CD14 + CD16and CD14 + CD16 + blood monocytes and BAL monocyte-derived cells as well as blood and BAL conventional DCs (cDC1 and cDC2) were processed for RNA sequencing. Briefly, data from patients were used and genes detected in fewer than 2 samples with counts per million (CPM) values lower than 1 were considered lowly expressed and removed from the analysis.…”

Section: Rna Sequencingmentioning

confidence: 99%

“…8 In sarcoidosis patients, circulating monocytes have been shown to have an inflammatory phenotype and can be used to predict disease outcome of patients. 9 Monocytes entering tissues have different fates.…”

Section: Introductionmentioning

confidence: 99%

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Pulmonary and blood dendritic cells from sarcoidosis patients more potently induce IFNγ-producing Th1 cells compared with monocytes

Lepzien

Nie

Czarnewski

et al. 2021

Journal of Leukocyte Biology

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Sarcoidosis is a systemic inflammatory disease mainly affecting the lungs. The hallmark of sarcoidosis are granulomas that are surrounded by activated T cells, likely targeting the disease-inducing antigen. IFNγ-producing Th1 and Th17.1 T cells are elevated in sarcoidosis and associate with disease progression. Monocytes and dendritic cells (DCs) are antigen-presenting cells (APCs) and required for T cell activation. Several subsets of monocytes and DCs with different functions were identified in sarcoidosis. However, to what extent different monocyte and DC subsets can support activation and skewing of T cells in sarcoidosis is still unclear. In this study, we performed a transcriptional and functional side-by-side comparison of sorted monocytes and DCs from matched blood and bronchoalveolar lavage (BAL) fluid of sarcoidosis patients.Transcriptomic analysis of all subsets showed upregulation of genes related to T cell activation and antigen presentation in DCs compared with monocytes. Allogeneic T cell proliferation was higher after coculture with monocytes and DCs from blood compared with BAL and DCs induced more T cell proliferation compared with monocytes.After coculture, proliferating T cells showed high expression of the transcription factor Tbet and IFNγ production. We also identified Tbet and RORγt coexpressing T cells that mainly produced IFNγ. Our data show that DCs rather than monocytes from sarcoidosis patients have the ability to activate and polarize T cells towards Th1 and Th17.1 cells. This study provides a useful in vitro tool to better understand the contribution of monocytes and DCs to T cell activation and immunopathology in sarcoidosis.

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Metabolomics and Transcriptomic Approach to Understand the Pathophysiology of Interstitial Lung Disease

Dasgupta,

Bhattacharya,

Choudhury

et al. 2023

Clinical Metabolomics Applications in Genetic Diseases

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Monocytes in sarcoidosis are potent tumour necrosis factor producers and predict disease outcome

Cited by 31 publications

References 48 publications

Hypoxia Promotes a Mixed Inflammatory-Fibrotic Macrophages Phenotype in Active Sarcoidosis

Hypoxia Promotes a Mixed Inflammatory-Fibrotic Macrophages Phenotype in Active Sarcoidosis

Pulmonary and blood dendritic cells from sarcoidosis patients more potently induce IFNγ-producing Th1 cells compared with monocytes

Metabolomics and Transcriptomic Approach to Understand the Pathophysiology of Interstitial Lung Disease

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