Single-cell gene expression profiles of lung cells from HCQ-treated mice.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE311755 | GEO | 2026/01/10
REPOSITORIES: GEO
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Project description:We performed single-cell RNA sequencing (scRNA-seq) of granulocyte-macrophage colony-stimulating factor (GM-CSF) cultured bone marrow cells (GM-BMCs) treated with hydroxychloroquine (HCQ) or cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) to reveal a divergence of the gene expression pattern in interferon β (IFNβ)-expressing cells between HCQ and cGAMP treatments.
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Project description:We performed RNA sequencing (RNA-seq) of granulocyte-macrophage colony-stimulating factor (GM-CSF) cultured bone marrow cells (GM-BMCs) treated with hydroxychloroquine (HCQ) or cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) to compare the gene expression profiles between HCQ and cGAMP treatments in GM-BMCs.
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Project description:Based on the consistent demonstration of fibrosis of the atrioventricular node surrounded by macrophages and multinucleated giant cells in anti-Ro antibody exposed fetuses dying with heart block, this study focuses on macrophage signaling stimulated by ssRNA associated with the Ro60 protein and the impact of antagonizing innate cell drivers such as TLR7/8. Transcriptome and epigenetic modifications which affect transcription factors, NF-κB and STAT1, were selected to evaluate the phenotype of macrophages in which TLR7/8 was ligated following treatment with either anti-Ro60/Ro60/hY3 RNA immune complexes or transfection with hY3. Based on microarray, TNF and IL6 were among the most highly upregulated genes in both stimulated conditions, each of which was significantly inhibited by preincubation with hydroxychloroquine (HCQ). In contrast, following stimulation of macrophages with either TNF-α or IFN-α, which do not signal through TLR, the resultant gene expression was refractory to HCQ. Ligation of TLR7/8 resulted in increased histone methylation as measured by increased H3K4me2, a requirement for binding of NF-κB at certain promoters, specifically the kB1 region in the TNF promoter (ChIP-qPCR), which was significantly decreased by HCQ. In summary, these results support that the HCQ-sensitive phenotype of hY3 stimulated macrophages reflects the bifurcation of TLR downstream signals involving NF-κB and STAT 1 pathways and for the former dimethylation of H3K4. Accordingly, HCQ may act more as a preventive measure in downregulating the initial production of IFN-α or TNF-α and not affect the resultant autocoid stimulation reflected in TNF-α and IFN-α responsive genes. The beneficial scope of antimalarials in the prevention of organ damage, inclusive of heart block in an anti-Ro offspring or more broadly SLE, may include in part, a mechanism targeting TLR-dependent epigenetic modification.
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Project description:Cells were treated with either PBS (mock) or hydroxychloroquine (HCQ).
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Project description:Cells were treated with either PBS (mock) or hydroxychloroquine (HCQ).
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Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of premature death for patients with Neurofibromatosis type 1 and no approved targeted therapies are available. Benign plexiform neurofibromas have been successfully treated with selumetinib, a MEK inhibitor, but after progression to MPNST, MEK inhibition alone is not effective. Frequently, adaptive responses to single agent targeted inhibitors invokes alterations in receptor tyrosine kinase expression and feedback regulation that leads to inhibitor bypass. Here, the effects of SHP099, an inhibitor of the protein-tyrosine phosphatase SHP2 (encoded by the PTPN11 gene) was tested alone and in combination with trametinib (MEKi) in an NF1 MPNST patient derived xenograft model (PDX4) treated with SHP099, hydroxychloroquine (HCQ) or the combination. Kinase enrichment proteomic analysis was performed using tumor tissue treated with SHP099, hydroxychloroquine (HCQ) or the combination to evaluate the effects on the functional kinome.
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Project description:Hydroxychloroquine (HCQ) is an autophagy inhibitor that has been used for the treatment of many diseases, such as malaria, rheumatoid arthritis, systemic lupus erythematosus, cancer, and so on. Despite the therapeutic advances in these diseases, the underlying mechanisms have not been well determined and hinder the rational use of this drug in the future. Here, we explored the possible mechanisms and identified the potential binding targets of HCQ by performing quantitative proteomics and thermal proteome profiling on MIA PaCa-2 cells. This study revealed that HCQ may exert its functions by targeting or regulating the expression of some autophagy-related proteins, such as galectin-8 (LGALS8), mitogen-activated protein kinase 8 (MAPK8), Ribosyldihydronicotinamide dehydrogenase (NQO2), Transport protein Sec23A (SEC23A), and so on. Furthermore, HCQ may prevent the progression of pancreatic cancer by regulating the expression of Nesprin-2 (SYNE2), Protein-S-isoprenylcysteine O-methyltransferase (ICMT) and Cotranscriptional regulator FAM172A (FAM172A). Therefore, these findings not only identify potential binding targets for HCQ but also revealed the non-canonical mechanisms of HCQ that may contribute to pancreatic cancer treatment.
2022-10-13 | PXD034196 | Pride
Project description:Objective: Patients with Systemic Lupus Erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III interferon (IFN) in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC, and how this production can be regulated. Methods: Peripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1 associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA-sequencing of pDCs using ddSEQ technology was performed. Results: Type III IFN mRNA and protein was induced in RNA-IC stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6 or granulocyte-macrophage colony stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2-5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p<0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%. Conclusions: Type III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.
2020-05-23 | GSE149415 | GEO
Project description:Objective: Patients with Systemic Lupus Erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III interferon (IFN) in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC, and how this production can be regulated. Methods: Peripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1 associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA-sequencing of pDCs using ddSEQ technology was performed. Results: Type III IFN mRNA and protein was induced in RNA-IC stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6 or granulocyte-macrophage colony stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2-5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p<0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%. Conclusions: Type III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.
2020-05-23 | GSE148902 | GEO
Project description:Purpose: To investigate the inhibition of inflammatoty cytokines of Hydroxychloroquine to phagocytic THP-1 cells. Methods: we established a cell model of hemophagocytosis by simulating THP-1 cells with CpG-c for 24h in vitro to produce macrophages, and then coculture the cells with human RBCs. RNA sequencing analysis of THP-1 cells were performed to find Gene changed with CpG-c stimulation and Hydroxychloroquine intervention. Results:CpG-c sitimulation significantly altered gene expression of THP-1 cells. Cytokine genes were upregulated, especially a significant increase in IL-6 level from scratch. HCQ significantly inhibited the expression of inflammatory cytokines and decreased IL-6 gene level to baseline. Conclusions:Hydroxychloroquine can inhibite cytokine genes, especially IL-6 Gene level of THP-1 cells caused by CpG-c sitimulation.
2022-07-01 | GSE198290 | GEO