Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lung of severe COVID-19 patients

ABSTRACT: Hyperinflammation contributes to lung injury and subsequent acute respiratory distress syndrome (ARDS) with high mortality in severe COVID-19. To understand the underlying mechanisms, we investigated the role of the lung-specific immune response. Here we profiled lymphocytes and myeloid cells in the bronchoalveolar lavage (BAL) fluid and blood of COVID-19 patients. By tracking T cell clones across tissues, we identified clonally expanded tissue-resident memory-like Th17 cells (Trm17 cells) in the lung even after viral clearance. These Trm17 cells are characterized by a potentially pathogenic cytokine profile with expression of IL17A and CSF2 (GM-CSF). Interactome analysis revealed that Trm17 cells interact with macrophages and cytotoxic CD8+ T cells, which have been associated with disease severity and lung damage. High IL-17A and GM-CSF protein levels in the serum of COVID-19 patients correlated with severe clinical course. This study suggests pulmonary Trm17 cells as one of the orchestrators of the hyperinflammation in severe COVID-19 and that these cells and their cytokines, such as GM-CSF, are promising biomarkers and potential targets for a COVID-19 therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167118 | GEO | 2021/02/20

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Loss of GM-CSF-dependent instruction of alveolar macrophages in COVID-19 provides a rationale for inhaled GM-CSF treatment (RNA-Seq)

Project description:Systemic GM-CSF promotes myelopoiesis and inflammation and GM-CSF blockade is being evaluated as treatment for COVID-19-associated hyperinflammation. Alveolar GM-CSF is however required for monocytes to differentiate into alveolar macrophages (AM) that control alveolar homeostasis and dampen inflammation. By mapping cross-species AM development stages to clinical lung samples, we discovered that COVID-19 is marked by defective GM-CSF-dependent AM instruction and accumulation of proinflammatory macrophages. In a multi-center, open-label, randomized, controlled trial in 81 non-ventilated COVID-19 patients with respiratory failure, we found that inhalation of rhu-GM-CSF did not improve mean oxygenation parameters compared with standard treatment. However, more patients on GM-CSF had a clinical response, and GM-CSF inhalation induced higher numbers of virus-specific CD8 effector lymphocytes and class-switched B cells, without exacerbating systemic hyperinflammation. This translational proof-of-concept study provides rationale for further testing of inhaled GM-CSF as non-invasive treatment to improve alveolar gas exchange and simultaneously boost anti-viral immunity in COVID-19

2022-11-03 | GSE216704 | GEO

Loss of evolutionary conserved GM-CSF-dependent signature in pulmonary macrophages in COVID-19 provides a rationale for inhaled GM-CSF treatment (microarray)

Project description:Alveolar GM-CSF is required for monocytes to differentiate into alveolar macrophages (AM) that control alveolar homeostasis and dampen inflammation. By mapping cross-species AM development stages to clinical lung samples, we discovered that COVID-19 is marked by defective GM-CSF-dependent AM instruction and accumulation of proinflammatory macrophages. In a multi-center, open-label, randomized, controlled trial in 81 non-ventilated COVID-19 patients with respiratory failure, we found that inhalation of rhu-GM-CSF did not improve mean oxygenation parameters compared with standard treatment. However, more patients on GM-CSF had a clinical response, and GM-CSF inhalation induced higher numbers of virus-specific CD8 effector lymphocytes and class-switched B cells, without exacerbating systemic hyperinflammation. This translational proof-of-concept study provides rationale for further testing of inhaled GM-CSF as non-invasive treatment to improve alveolar gas exchange and simultaneously boost anti-viral immunity in COVID-19

2022-11-03 | GSE216701 | GEO

Sca1+ macrophages activate hematopoietic stem/progenitor cells upon bone marrow stress. [scRNA-Seq]

Project description:Although hematopoietic stem and progenitor cells (HSPCs) become activated in the cell-cycle status after chemotherapy to supply hematopoietic loss, the detailed mechanisms of activation remain unknown. Here we show that Sca1+ macrophages play a key role for bone marrow (BM) recovery through granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. By analyzing gene expression profiles of HSPCs lodged in 5-fluolouracil (5-FU)-treated mice, we found GM-CSF as a key proliferative signal. Sca1+ macrophages in BM after 5-FU treatment expressed high levels of GM-CSF. GM-CSF-knockout mice treated with 5-FU were lethal because of severe BM suppression. Up-regulation of Csf2 in Sca1+ macrophages by 5-FU was suppressed in MyD88-knockout mice, suggesting that TLR signaling via damage-associated molecular patterns caused by cell death is critical for up-regulation of Csf2. In 5-FU treated BM, majority of Sca1+ macrophages and transplanted HSPCs locate perivascular areas. These findings together indicate that Sca1+ macrophages induce HSPCs to proliferate through GM-CSF signaling in the stressed BM environments.

2021-01-20 | GSE120112 | GEO

Sca1+ macrophages activate hematopoietic stem/progenitor cells upon bone marrow stress. [RNA-Seq]

2021-01-20 | GSE120111 | GEO

Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage [scRNA-seq]

Project description:Recent studies of severe acute inflammatory lung disease including COVID-19 have identified macrophages to drive pulmonary hyperinflammation and long-term damage such as fibrosis. Here, we report on the development of a first-in-class, carbohydrate-coupled inhibitor of microRNA-21 (RCS-21), as a therapeutic means against pulmonary hyperinflammation and fibrosis. MicroRNA-21 was among the strongest upregulated microRNAs in COVID-19 and in mice with acute inflammatory lung damage and was the strongest expressed microRNA in pulmonary macrophages. Chemical linkage of an oligonucleotide inhibitor of microRNA-21 to trimannose achieved rapid and specific delivery to macrophages upon inhalation in mice. RCS-21 reversed pathological activation of macrophages and prevented pulmonary dysfunction and fibrosis after acute lung damage in mice. In human lung tissue infected with SARS-CoV-2 ex vivo, RCS-21 effectively prevented the exaggerated inflammatory response. Our data imply trimannose-coupling for effective and selective delivery of inhaled oligonucleotides to pulmonary macrophages and report on a first mannose-coupled candidate therapeutic for COVID-19.

2023-07-12 | GSE235135 | GEO

Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage [transcriptome_mouse]

2023-07-12 | GSE235134 | GEO

Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage [transcriptome_human_COVID]

2023-07-12 | GSE235133 | GEO