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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235130 | GEO | 2023/07/12

REPOSITORIES: GEO

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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

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

2023-07-12 | GSE235132 | GEO

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

2023-07-12 | GSE235131 | GEO

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

Project description: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.

2021-02-20 | GSE167118 | GEO

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

Synthetic Siglec-9 agonists inhibit neutrophil activation associated with COVID-19

Project description:Severe cases of coronavirus disease 2019 (COVID-19) are characterized by a hyperinflammatory immune response that leads to numerous complications. Production of proinflammatory neutrophil extracellular traps (NETs) has been suggested to be a key factor in inducing a hyperinflammatory signaling cascade, allegedly causing both pulmonary tissue damage and peripheral inflammation. If true, finding ways to inhibit NET production could provide therapeutic strategies to prevent respiratory damage and death from SARS-CoV-2 related inflammation. Here, we demonstrate that synthetic glycopolymers that activate signaling of the neutrophil checkpoint receptor Siglec-9 suppress NETosis induced by agonists of viral TLR receptors and COVID-19 plasma. Thus, Siglec-9 represents an attractive therapeutic target to curb neutrophilic hyperinflammation in COVID-19.

2021-07-28 | PXD022990 | Pride

Persistent viral activity, cytokine storm and lung fibrosis in severe COVID-19

Project description:Severe COVID-19 may progress into acute respiratory distress syndrome (ARDS) with high mortality risk. Its exact pathological mechanism, therapeutic obstacles and the clinical sequelae are critical and unresolved issues. Here, we reported a representative COVID-19 induced ARDS case experienced initially stable, then suddenly deteriorating up to final respiratory failure courses, until his death despite of lung transplantation. His lung pathology showed necrosis of parenchymal tissues, extensive immune cell infiltration and lung fibrosis. Single-cell RNA sequencing revealed various immune cell populations were largely expanded in his lung, and manifested inflammatory/activated functions. We also showed that cell-crosstalk between lung macrophages and fibroblasts promoted pulmonary fibrosis through IL-1B and TGF-Β signaling pathways. Although SARS-CoV-2 RNA remained undetectable in his respiratory tract specimens including BALF at the later stage of his disease, the presence of SARS-CoV-2 was definitely confirmed in his lung tissues. Thus, this case indicates the pathological mechanism of severe COVID-19 includes pulmonary SARS-CoV-2 persistence, deranged inflammation and the extensive lung fibrosis which set the barriers for effective treatments and indicate potential health complications for severe COVID-19 patients.

2020-12-01 | GSE149878 | GEO

Next generation sequencing transcriptome analysis of patient-derived macrophages stimulated with SARS-CoV-2 protein

Project description:Innate immunity triggers responsible for viral control or hyperinflammation in COVID-19 are largely unknown. Here we show that the SARS-CoV-2 spike protein (S-protein) primes inflammasome formation and release of mature interleukin-1β (IL-1β) in macrophages derived from COVID-19 patients but not in macrophages from healthy SARS-CoV-2 naïve individuals. Furthermore, longitudinal analyses reveal robust S-protein driven inflammasome activation in macrophages isolated from convalescent COVID-19 patients, which correlates with distinct epigenetic and gene-expression signatures suggesting innate immune memory after recovery from COVID-19. Importantly, we show that S-protein driven IL-1β secretion from patient-derived macrophages requires non-specific monocyte pre-activation in vivo to trigger NLRP3-inflammasome signaling. Our findings reveal that SARS-CoV-2 infection causes profound and long-lived re-programming of macrophages resulting in augmented immunogenicity of the SARS-CoV-2 S-protein, a major vaccine antigen and potent driver of adaptive and innate immune signaling.

2021-06-07 | GSE173488 | GEO

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