IFN-gamma is essential for alveolar macrophage driven pulmonary inflammation in macrophage activation syndrome
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ABSTRACT:
PROVIDER: PRJNA716274 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14032940.fastq.gz | Fastqsanger.gz | |||
| SRR14032941.fastq.gz | Fastqsanger.gz | |||
| SRR14032942.fastq.gz | Fastqsanger.gz | |||
| SRR14032943.fastq.gz | Fastqsanger.gz |
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Project description:Macrophage activation syndrome (MAS) is a life-threatening cytokine storm syndrome complicating systemic juvenile idiopathic arthritis (SJIA) and driven by IFN-gamma. SJIA and MAS are also associated with an unexplained emerging inflammatory lung disease (SJIA-LD), with our recent work supporting pulmonary activation of IFN-gamma pathways as a pathologic link between SJIA-LD and MAS. Our objective was to mechanistically define the novel observation of pulmonary inflammation in the TLR9 mouse model of MAS. In acute MAS, lungs exhibit mild but diffuse CD4-predominant, perivascular interstitial inflammation with elevated IFN-gamma, IFN-induced chemokines, and alveolar macrophage expression of IFN-gamma-induced genes. Single-cell RNA-sequencing confirmed IFN-driven transcriptional changes across immune and parenchymal lung cell types. Resolution of MAS was associated with increased alveolar macrophage and interstitial lymphocytic infiltration. alveolar macrophage microarrays confirmed IFN-gamma-induced proinflammatory polarization during acute MAS, which switches towards an anti-inflammatory phenotype during MAS resolution. Interestingly, recurrent MAS led to increased alveolar inflammation and lung injury, and reset alveolar macrophagepolarization towards a proinflammatory state. Furthermore, in mice bearing macrophages insensitive to IFN-gamma, both systemic feature of MAS and pulmonary inflammation were attenuated. These findings demonstrate that experimental MAS induces IFN-gamma-driven pulmonary inflammation replicating key features of SJIA-LD, and provides a model system for testing novel treatments directed towards SJIA-LD.
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Project description:we studied the role of exosomes isolated from M.tb infected macrophages in modulating the macrophage response to IFN-γ. Nimblegen microarray gene expression studies were used to compare the suppression of IFN-γ inducible genes by exosomes relative to the virulent strain of M.tuberculosis. Overall our study suggest that exosomes, as carriers of M.tb pathogen associated molecular patterns (PAMPs), may provide a mechanistic link by which M.tb may exert its suppression of host immune response beyond the infected cell, and implies a physiological role for exosomes in immune surveillance of TB. Macrophages were treated with exosomes, infected with M.tb H37Rv or left untreated for 18 hours followed by +/- IFN-γ for an additional 18 hours. Cells were harvested and RNA was isolated and converted to double stranded cDNA and subsequently labeled and hybridized onto Mus musculus 4×72 Nimblegen microarray using Nimblegen Hybridization system 4 according to manufacturer’s instructions (Roche)
2011-06-05 | E-GEOD-29731 | biostudies-arrayexpress
Project description:Macrophages are major effector cells and antigen presenting cells of the innate immune system and classical activation of macrophage function requires interferon–γ (IFN-γ) pretreatment (priming) and TLR stimuli, which promotes inflammatory responses though high levels of pro-inflammatory cytokines and lower level of the anti-inflammatory cytokines, resulting in microbicidal and tumoricidal effect. However, the underlying molecular mechanism of IFN-γ priming remains elusive. In this study, we explored the effect of IFN-γ on macrophages at miRNA level and discovered that miR-3473b, which was down-regulated after IFN-γ priming, could attenuate the priming effect of IFN-γ. Molecular study revealed that miR-3473b promoted Akt/GSK3 signaling and IL-10 production through directly targeting PTEN to suppress inflammatory response and tumor-suppressing capability of macrophages. In summary, our data demonstrate that IFN-γ beef up macrophage inflammatory response and tumor suppressing capacity by limiting miR-3473b-mediated PTEN suppression. Our work identified an IFN-γ/miR-3473b/Akt axis in the regulation of macrophage function and activation. the assay was performed with 5 μg total RNA samples from both normal BMM (labeled by Cy3) and BMM primed by IFN-γ (100U/ml) for 4 h(labeled by Cy5), normal BMM serves as control.
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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-.
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Project description:Granuloma annulare (GA) and cutaneous sarcoidosis (cSAR), non-communicable skin conditions, possess an overlapping immunopathology, in which the aberrant activation of macrophages by IFN-γ constitutes a central driver of disease. Nevertheless, our understanding of the molecular events occurring in pathologically activated GA and cSAR macrophages remains limited. Here, we analyzed published single-cell RNA sequencing data of GA and cSAR and performed in-vitro experiments with primary human cells, allowing us to show that oxidative phosphorylation (OXPHOS) is a dominant metabolic pathway in IFN-γ-activated macrophages. Furthermore, we identify an IFN-γ-induced, OXPHOS-sensitive response network in human GA and cSAR macrophages. Within this network, GBP1 plays a central role in controlling IFN-γ-mediated macrophage activation. Meanwhile, inhibition of OXPHOS and GBP1 both promoted resolution of granulomas and prevented granuloma induction in a human in-vitro granuloma model. Taken together, our study suggests that OXPHOS and GBP1 represent therapeutic strategies for treating cutaneous granulomatous diseases.
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Project description:Macrophages are major effector cells and antigen presenting cells of the innate immune system and classical activation of macrophage function requires interferon–γ (IFN-γ) pretreatment (priming) and TLR stimuli, which promotes inflammatory responses though high levels of pro-inflammatory cytokines and lower level of the anti-inflammatory cytokines, resulting in microbicidal and tumoricidal effect. However, the underlying molecular mechanism of IFN-γ priming remains elusive. In this study, we explored the effect of IFN-γ on macrophages at miRNA level and discovered that miR-3473b, which was down-regulated after IFN-γ priming, could attenuate the priming effect of IFN-γ. Molecular study revealed that miR-3473b promoted Akt/GSK3 signaling and IL-10 production through directly targeting PTEN to suppress inflammatory response and tumor-suppressing capability of macrophages. In summary, our data demonstrate that IFN-γ beef up macrophage inflammatory response and tumor suppressing capacity by limiting miR-3473b-mediated PTEN suppression. Our work identified an IFN-γ/miR-3473b/Akt axis in the regulation of macrophage function and activation.
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