Interferon (IFN)-γ promotes monocyte-mediated lung injury during influenza pathogenesis
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PROVIDER: PRJNA782962 | ENA |
REPOSITORIES: ENA
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Project description:Influenza A Virus (IAV) triggers an exuberant host response that promotes acute lung injury. However, the determinants of the pathological host response to IAV remain incompletely understood. In the current study, we identified interferon (IFN)-γ-regulated subset of monocytes, CCR2+ monocytes, as a driver of lung damage during IAV pathogenesis. IFN-γ regulated the recruitment and inflammatory phenotype of CCR2+ monocytes, and CCR2 (CCR2-/-) and IFN-γ (IFN-γ-/-) deficient mice exhibited reduced lung inflammation, pathology, and increased resistance against bacterial co-infection by Streptococcus pneumoniae (Spn). Adoptive transfer of WT (IFN-γR1+), but not IFN-γR1 deficient (IFN-γR1-) CCR2+ monocytes, restored the wild-type (WT)-like pathological phenotype of lung damage in IAV-infected CCR2-/- mice. The CD8+ T cells were the most significant source of IFN-γ in IAV-infected lungs. Collectively, our data highlight that IFN-γ regulates CCR2+ monocyte-mediated lung pathology during IAV pathogenesis.
2021-11-25 | GSE189407 | GEO
Project description:A growing body of evidence suggests that inflammatory cytokines have a dualistic role in immunity. In this study, we sought to determine the direct effects IFN-gamma on the differentiation and maturation of human peripheral blood monocyte-derived dendritic cells (moDC). Here, we report that following differentiation of human peripheral-blood monocytes into moDCs with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4, interferon-gamma (IFN-gamma) induces moDC maturation and up-regulates the co-stimulatory markers CD80, CD86, CD95, and MHC Class I, enabling moDCs to effectively generate antigen-specific CD4+ and CD8+ T cell responses for multiple viral and tumor antigens. Interestingly, early exposure of monocytes to high concentrations of IFN-gamma promotes monocyte differentiation into macrophages, despite the presence of GM-CSF and IL-4. However, under low concentrations of IFN-gamma, monocytes continue to differentiate into dendritic cells possessing a unique gene-expression profile, resulting in impairments in subsequent maturation by IFN-gamma and an inability to generate effective antigen-specific CD4+ and CD8+ T cell responses compared to standard moDCs. Monocytes differentiated in the presence of low levels of IFN-gamma downregulate IFN-gamma receptor expression, impairing their response to an inflammatory rechallenge. These findings demonstrate the ability of IFN-gamma to impart differential programs on human moDCs which shape the antigen-specific T cell responses they induce. Timing and intensity of exposure to IFN-gamma can thus determine whether moDCs are tolerogenic or immunostimulating. Human monocyte-derived dendritic cells from 4 healthy donors were differentiated with either GM-CSF and IL-4 (n=4) or GM-CSF, IL-4, and IFN-gamma (n=4). These samples were subsequently hybridized to arrays as 4 biological repeats for each of the two treatment conditions.
2014-06-01 | E-GEOD-47621 | biostudies-arrayexpress
Project description:Glucocorticoids are extensively used to treat inflammatory diseases, however their chronic intake increases the risk of mycobacterial infections. Meanwhile, the effects of glucocorticoids on innate host responses are incompletely understood. Here, we studied the direct effects of glucocorticoids on antimycobacterial host defense in primary human macrophages. We found that glucocorticoids triggered the expression of cathelicidin, an antimicrobial critical for antimycobacterial response, independent of the intracellular vitamin D metabolism. Despite upregulating cathelicidin, glucocorticoids failed to promote macrophage antimycobacterial activity. Gene expression profiles of human macrophages treated with glucocorticoids and/or IFN-gamma, which promotes induction of cathelicidin, as well as antimycobacterial activity, were investigated. Using weighted gene coexpression network analysis (WGCNA), we identified a module of highly connected genes that was strongly inversely correlated with glucocorticoid treatment and associated with IFN-gamma stimulation. This module was linked to the biological functions âautophagyâ, âphagosome maturationâ and âlytic vacuole/lysosomeâ, and contained the vacuolar H+-ATPase (v-ATPase) subunit a3, alias TCIRG1, a known antimycobacterial host defense gene, as a top hub gene. We next found that glucocorticoids, in contrast to IFN-gamma, failed to trigger expression and phagolysosome recruitment of TCIRG1, as well as to promote lysosome acidification. Finally, we demonstrated that the tyrosine kinase inhibitor imatinib induces lysosome acidification and antimicrobial activity in glucocorticoid-treated macrophages without reversing the anti-inflammatory effects of glucocorticoids. Taken together, we provide evidence that the induction of cathelicidin by glucocorticoids is not sufficient for macrophage antimicrobial activity, and identify the v-ATPase as a potential target for host-directed therapy in the context of glucocorticoid therapy. Peripheral blood mononuclear cells (PBMCs) of three healthy human donors were isolated by Ficoll-Paque (GE Healthcare). Monocytes were isolated via CD14+ MACS cell separation (Miltenyi Biotec) according to the manufacturers instructions. Monocyte-derived macrophages (MDMs) were prepared by culturing peripheral blood monocytes in RPMI media containing 10% FCS for four to seven days in the presence of M-CSF (50 ng/ml). Afterwards cells were cultured in fresh media with 10% vitamin D-sufficient human AB serum. Cells were stimulated with media, dexamethasone, interferon-gamma and dexamethasone/interferon-gamma for 20h. Total RNA of was isolated with TRIZOL (Life Technologies) and RNA quality was confirmed using micro capillary electrophoresis (2100 Bioanalyzer, Agilent). 100ng RNA was labeled and hybridized to Sureprint G3 human GE 8x60K whole genome mRNA microarray according to the manufacturerâs specifications. The arrays were scanned (Agilent G2595C scanner), data extracted and processed using the Genespring XII software (Agilent).
2016-05-30 | E-GEOD-79077 | biostudies-arrayexpress
Project description:SP110b is an interferon (IFN)-induced nuclear protein and may function as a transcriptional co-activator/repressor. IFNγ activates monocytes/macrophages thereby mediating inflammation. However, uncontrolled activation induces monocyte/macrophage cell death, which may cause immunopathology. We have demonstrated that SP110b expression prevented IFNγ-mediated monocyte/macrophage cell death. To explore the molecular mechanisms by which SP110b suppresses IFNγ-induced cell death, we performed a genome-wide microarray analysis to identify genetic determinants associated with IFNγ-induced cell death and regulated by SP110b.
2015-05-18 | GSE58096 | GEO
Project description:This study demonstrates quantitative and qualitative differences between type I IFN signatures in autoimmunity and viral infection using purified CD4pos T cells and CD16pos- and CD16neg-monocyte subsets. We were able to discriminate between cell-specific viral response signatures and the pathogenically amplified IFN signatures observed in autoimmunity. The differences were of both a qualitative and quantitative nature, as the signatures in the patients with SLE were characterized by much more complexly compiled gene patterns with increased absolute gene expression levels.
2014-01-06 | GSE51997 | GEO
Project description:SP110b is an interferon (IFN)-induced nuclear protein and may function as a transcriptional co-activator/repressor. IFNγ activates monocytes/macrophages thereby mediating inflammation. However, uncontrolled activation induces monocyte/macrophage cell death, which may cause immunopathology. We have demonstrated that SP110b expression prevented IFNγ-mediated monocyte/macrophage cell death. To explore the molecular mechanisms by which SP110b suppresses IFNγ-induced cell death, we performed a genome-wide microarray analysis to identify genetic determinants associated with IFNγ-induced cell death and regulated by SP110b. We sought to identify genetic determinants associated with IFNγ-induced cell death and regulated by SP110b. To that end, THP1 human monocyte-like cells that could be induced by doxycycline (Dox) to over-express SP110b (THP1-SP110b) were generated and 5 experimental groups of THP1-SP110b cells were harvested for RNA extraction and hybridization on Affymetrix microarrays. The 5 groups are as follows: untreated THP1-SP110b cells as control (CON), cells treated with IFNγ for 2 days (IFN_2D), cells treated with Dox plus IFNγ for 2 days (DoxIFN_2D), cells treated with IFNγ for 4 days (IFN_4D), and cells treated with Dox plus IFNγ for 4 days (DoxIFN_4D).
2015-05-18 | E-GEOD-58096 | biostudies-arrayexpress
Project description:A growing body of evidence suggests that inflammatory cytokines have a dualistic role in immunity. In this study, we sought to determine the direct effects IFN-gamma on the differentiation and maturation of human peripheral blood monocyte-derived dendritic cells (moDC). Here, we report that following differentiation of human peripheral-blood monocytes into moDCs with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4, interferon-gamma (IFN-gamma) induces moDC maturation and up-regulates the co-stimulatory markers CD80, CD86, CD95, and MHC Class I, enabling moDCs to effectively generate antigen-specific CD4+ and CD8+ T cell responses for multiple viral and tumor antigens. Interestingly, early exposure of monocytes to high concentrations of IFN-gamma promotes monocyte differentiation into macrophages, despite the presence of GM-CSF and IL-4. However, under low concentrations of IFN-gamma, monocytes continue to differentiate into dendritic cells possessing a unique gene-expression profile, resulting in impairments in subsequent maturation by IFN-gamma and an inability to generate effective antigen-specific CD4+ and CD8+ T cell responses compared to standard moDCs. Monocytes differentiated in the presence of low levels of IFN-gamma downregulate IFN-gamma receptor expression, impairing their response to an inflammatory rechallenge. These findings demonstrate the ability of IFN-gamma to impart differential programs on human moDCs which shape the antigen-specific T cell responses they induce. Timing and intensity of exposure to IFN-gamma can thus determine whether moDCs are tolerogenic or immunostimulating.
2014-06-01 | GSE47621 | GEO
Project description:Monocyte derived macrophages were exposed to arachidonic acid, interferon beta, or interferon gamma
2021-12-31 | E-MTAB-10867 | biostudies-arrayexpress
Project description:Inborn errors of human IFN-γ immunity underlie mycobacterial diseases, whereas inborn errors of IFN-/ immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe two unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-/ immunity. The IRF1-dependent cellular responses to IFN-γ are, both quantitatively and qualitatively, much greater than those to IFN-/ in vitro. Monocyte- and iPSC-derived macrophages from the two patients show no upregulation of at least 20% of the target genes normally induced by IFN-γ. By contrast, cell-intrinsic IFN-/ immunity to diverse viruses, including SARS-CoV-2, is intact. Human IRF1 is, thus, largely redundant for antiviral IFN-/ immunity. By contrast, human IRF1 is essential for IFN-γ immunity to mycobacteria in myeloid cells.
2023-01-12 | GSE218033 | GEO
Project description:Systemic juvenile idiopathic arthritis (SJIA) confers high risk for macrophage activation syndrome (MAS), a life-threatening episode of hyperinflammation driven by IFN-γ. Monocytes in SJIA display IFN-γhyperresponsiveness, but the molecular basis of this remains unclear. The objective of this study is to identify monocyte and macrophage polarization phenotypes including features of interferon response. Bulk RNA-seq of purified SJIA monocytes revealed marked transcriptional changes in patients with elevated ferritin levels. We identified substantial overlap with multiple polarization states but little evidence of IFN-induced signature. Interestingly, among the most highly upregulated genes was tripartite motif containing 8 (TRIM8), a positive regulator of IFN-γ signaling. Single cell RNA-seq of bone marrow macrophages (BMM) from a patient with SJIA and early MAS identified a distinct subpopulation of BMM with altered transcriptomes consistent with hemophagocytes, including upregulated IFN-γ response pathways. These BMM also showed significantly increased expression of TRIM8. In vitro knock-down of TRIM8 in macrophages caused significant reductions in IFN-γ responsiveness. In conclusions, we identify a clear IFN-γ response phenotype in BMM during MAS. TRIM8 is upregulated in both monocytes and macrophages in SJIA, and required for macrophage IFN-γ response in vitro, providing a molecular mechanism and novel therapeutic for monocyte hyperresponsiveness to IFN-.
2021-02-02 | GSE147795 | GEO