Combined phosphoproteome and transcriptome analysis of the macrophage response to mycobacterial cord factor reveals a dichotomy of MINCLE-dependent and -independent signaling
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ABSTRACT:
PROVIDER: PRJNA474533 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7257550.fastq.gz | Fastqsanger.gz | |||
| SRR7257551.fastq.gz | Fastqsanger.gz | |||
| SRR7257552.fastq.gz | Fastqsanger.gz | |||
| SRR7257553.fastq.gz | Fastqsanger.gz | |||
| SRR7257554.fastq.gz | Fastqsanger.gz |
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Project description:Immune sensing of Mycobacterium tuberculosis relies on recognition by macrophages. Mycobacterial cord factor, trehalose-6,6’-dimycolate (TDM), is the most abundant cell wall glycolipid and binds to the C-type lectin receptor (CLR) MINCLE. To explore the kinase signaling linking the TDM-MINCLE interaction to gene expression, we employed quantitative phosphoproteome analysis. TDM caused upregulation of 6.7% and suppressed 3.8% of the 14,000 phospho-sites identified on 3727 proteins. MINCLE-dependent phosphorylation was observed for canonical players of CLR signaling (e.g. PLCg, PKCd), and was enriched for PKCd and GSK3 kinase motifs. MINCLE-dependent activation of the PI3K-AKT-GSK3 pathway contributed to inflammatory gene expression and required the PI3K regulatory subunit p85a. Unexpectedly, a substantial fraction of TDM-induced phosphorylation was MINCLE-independent, a finding paralleled by transcriptome data. Bioinformatic analysis of both datasets concurred in the requirement for MINCLE for innate immune response pathways and processes. In contrast, MINCLE-independent phosphorylation and transcriptome responses were linked to cell cycle regulation. Collectively, our global analyses show substantial reprogramming of macrophages by TDM and reveal a dichotomy of MINCLE-dependent and -independent signaling linked to distinct biological responses.
2019-06-01 | GSE115322 | GEO
Project description:Sensing of Mycobacterium tuberculosis by the immune system relies on recognition by macrophages. Mycobacterial cord factor, trehalose-6,6’-dimycolate (TDM), is the most abundant cell wall glycolipid and binds to the C-type lectin receptor Mincle. To explore the kinase signaling linking the TDM-Mincle interaction to gene expression, we employed quantitative phosphoproteome analysis using dimethyl-labeling and high-resolution mass spectrometry. TDM caused upregulation of 6.7% and suppressed 3.8% of the 14k phospho-sites identified in 3727 proteins. Mincle-dependent phosphorylation was observed for several canonical players of CLR signaling (e.g. PLC, PKC), and was enriched for PKC and GSK3 kinase motifs. Mincle-dependent activation of the PI3K-AKT-GSK3 pathway contributed to TDM-induced inflammatory gene expression and required the PI3K regulatory subunit p85. Unexpectedly, a substantial fraction of TDM-induced phosphorylation was Mincle-independent, a finding which was paralleled by RNAseq-based transcriptome data. GO and pathway enrichment analysis of both datasets concurred in the requirement for Mincle in “innate immune response”. In contrast, Mincle-independent phosphorylation and transcriptome responses to TDM were linked to “cell cycle” and to the DNA damage response. Collectively, our global analyses show substantial reprogramming of macrophages by mycobacterial cord factor and reveal a dichotomy of Mincle-dependent and –independent signaling linked to distinct biological responses
2019-01-17 | PXD009513 | Pride
Project description:Immune sensing of Mycobacterium tuberculosis relies on recognition by macrophages. Mycobacterial cord factor, trehalose-6,6'-dimycolate (TDM), is the most abundant cell wall glycolipid and binds to the C-type lectin receptor (CLR) MINCLE. To explore the kinase signaling linking the TDM-MINCLE interaction to gene expression, we employed quantitative phosphoproteome analysis. TDM caused upregulation of 6.7% and suppressed 3.8% of the 14,000 phospho-sites identified on 3727 proteins. MINCLE-dependent phosphorylation was observed for canonical players of CLR signaling (e.g. PLCγ, PKCδ), and was enriched for PKCδ and GSK3 kinase motifs. MINCLE-dependent activation of the PI3K-AKT-GSK3 pathway contributed to inflammatory gene expression and required the PI3K regulatory subunit p85α. Unexpectedly, a substantial fraction of TDM-induced phosphorylation was MINCLE-independent, a finding paralleled by transcriptome data. Bioinformatics analysis of both data sets concurred in the requirement for MINCLE for innate immune response pathways and processes. In contrast, MINCLE-independent phosphorylation and transcriptome responses were linked to cell cycle regulation. Collectively, our global analyses show substantial reprogramming of macrophages by TDM and reveal a dichotomy of MINCLE-dependent and -independent signaling linked to distinct biological responses.
| S-EPMC6442366 | biostudies-literature
Project description:Analysis of total RNAs from wild-type and Mincle-KO macrophages stimulated with TLR2 ligand and co-stimulated with TLR2 ligand and Mincle ligand. And analysis of total and polysomal RNAs from wild-type macrophages co-stimulated with TLR2 ligand and Mincle ligand in the presence or absence of DHS inhibitor (GC7). Mincle is a C-type lectin receptor for trehalose dimycolate, a mycobacterial cell wall component. And results provide insight into the crosstalk between the TLR2 and Mincle signaling pathways by RNA-seq assay and identifying potential targets of Mincle-mediated translational control by polysome profiling assay.
2016-07-10 | GSE70793 | GEO
Project description:Mycobacteria can survive and persist in macrophages despite triggering multiple pattern recognition receptors and strong T cell-derived IFN-gamma production. The mycobacterial cord factor trehalose-6,6-dimycolate binds the C-type lectin receptor Mincle and induces inflammatory gene expression through the Syk-Card9 pathway. It is well established that TDM and IFN-gamma synergize to induce expression of iNOS. However, the cord factor may also act to down-regulate IFN-gamma-induced responses and contribute to mycobacterial immune evasion. Here, we have investigated the cross-regulation of the macrophage transcriptome by IFN-gamma and by TDM, as well as its synthetic analog TDB. For genome-wide expression profiling, bone marrow derived macrophages (BMMs) from female C57BL/6 mice aged 6 to 8 weeks were used for stimulation.
2019-09-10 | GSE137150 | GEO
Project description:Macrophage-inducible C-type lectin (Mincle) dependent sensing of pathogens trig-gers proinflammatory immune responses in professional phagocytes that contribute to protect the host against pathogen invasion. Here, we examined whether overex-pression of Mincle designed to improve early pathogen sensing by professional phagocytes would improve lung protective immunity against Streptococcus pneu-moniae in mice. Proteomic profiling of alveolar macrophages (AM) of Mincle trans-genic (tg) mice stimulated with the Mincle-specific pneumococcal ligand glucosyl-diacylglycerol (Glc-DAG) revealed increased Nlrp3 inflammasome activation and downstream IL-1 cytokine release that was not observed in Glc-DAG stimulated Mincle KO or Nlrp3 KO macrophages. Along this line, Mincle tg mice also responded with a stronger Nlrp3 expression and early proinflammatory cytokine release after challenge with S. pneumoniae, ultimately leading to fatal pneumonia in the Mincle tg mice. Importantly, Nlrp3 inhibitor treatment of Mincle tg mice significantly mitigated the observed hyperinflammatory response to pneumococcal challenge. Together, we show that overexpression of the pattern recognition receptor Mincle triggers in-creased Glc-DAG dependent Nlrp3 inflammasome activation in professional phago-cytes leading to fatal pneumococcal pneumonia in mice, which is amenable to Nlrp3 inhibitor treatment. These data show that ectopic expression of Mincle receptor con-fers increased susceptibility rather than resistance to S. pneumoniae in mice, thus highlighting the importance of an inducible Mincle receptor expression in response to microbial challenge.
2020-10-05 | PXD018752 | Pride
Project description:Recent studies have demonstrated a strong association between acute kidney injury (AKI) and chronic kidney disease (CKD), while the unresolved inflammation is believed to be a driving force for this chronic transition process. As a transmembrane pattern recognition receptor, Mincle (macrophage-inducible C-type lectin, Clec4e) was identified to participate in the early immune response after AKI. However, the impact of Mincle on the chronic transition of AKI remains largely unclear. We performed single-cell RNA sequencing (scRNA-seq) with the unilateral ischemia-reperfusion (UIR) murine model of AKI at days 1, 3, 14 and 28 after injury. Potential effects and mechanism of Mincle on renal inflammation and fibrosis were further validated in vivo utilizing Mincle knockout mice. The dynamic expression of Mincle in macrophages and neutrophils throughout the transition from AKI to CKD was observed. For both cell types, Mincle expression was significantly up-regulated on day 1 following AKI, with a second rise observed on day 14. Notably, we identified distinct subclusters of Mincle-high neutrophils and Mincle-high macrophages that exhibited time-dependent influx with dual peaks characterized with remarkable pro-inflammatory and pro-fibrotic functions. Moreover, we identified that Mincle-high neutrophils represented an "aged" mature neutrophil subset derived from the "young" mature neutrophil cluster in kidney. Additionally, we observed a synergistic mechanism whereby Mincle-expressing macrophages and neutrophils sustained renal inflammation by augmenting tumor necrosis factor (TNF) production. Mincle-deficient mice exhibited reduced renal injury and fibrosis following AKI.
2024-05-23 | GSE267242 | GEO
Project description:Rat mast cell line RBL-2H3 was analyzed to investigate the molecular mechanism of Mincle-mediated activation and responses of mast cells. Mincle-mediated signaling stimulated characteristic gene expression, such as IL-3, IL-4, IL-9, IL-13, IL-31 and TNFα.
2016-04-20 | GSE80416 | GEO
Project description:Macrophage-inducible C-type lectin (Mincle, Clec4e) is a pathogen sensor that recognizes pathogenic fungi and Mycobactrium tuberculosis. We perfomed microarray analysis using peritoneal macrophages stimulated with TDM, a mycobacterial cell wall glycolipid that is known to be a Mincle ligand. Many chemokine and cytokine genes were upregulated in wildtype macrophages stimulated with TDM. Upregulation of these genes were completely abolishd in Mincle KO macrophages. Peritoneal macrophages from WT and Mincle KO mice were stimulated with TDM or vehicle for 24 h (3 samples each). Microarray analysis was performed using Affymetrix Mouse 430 2.0.
2013-11-14 | E-GEOD-52338 | biostudies-arrayexpress
Project description:This data set shows dramatic changes in gene expression in microglia isolated from C57Bl6/J mice subjected to transient middle cerebral artery occlusion, as compared to those subjected to sham surgery. Mice deficient in Mincle (Clec4e-/-) showed significantly improved injury outcomes 3 and 7 days after transient middle cerebral artery occlusion. However, when comparing changes in gene expression in microglia 24 hours after blood reperfusion, there were no differences between wild-type and Clec4e-/- mice, indicating that Mincle does not participate in early microglial activation. Wild type and Mincle knock-out (Clec4e-/-) mice. After 1 h of transient middle cerebral artery occlusion (tMCAO) and 24 h of reperfusion, mice were perfused with PBS, their brains dissected, and 2 ipsilesional hemispheres (with cerebellum and brainstem removed) pooled for microglia isolation. For sham-operated animals, the whole forebrain was used and brains were not pooled. After myelin separation by Percoll gradient centrifugation, around 80,000 CD45intermediate, CD11b+ microglial cells were sorted from each sample. Sham samples n=3, tMCAO samples n=5.
2016-03-24 | E-GEOD-77986 | biostudies-arrayexpress