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Mycobacterial cord factor reprograms the macrophage response to IFN-gamma towards enhanced inflammation yet impaired antigen presentation and expression of Gbp1

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE137150 | GEO | 2019/09/10

REPOSITORIES: GEO

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Combined phosphoproteome analysis of the response to mycobacterial cord factor reveals a dichotomy of Mincle-dependent and -independent signaling in macrophages

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

Card9 dependent activation of macrophages by TDB

Project description:Bone marrow derived macrophages from wt and card9 KO mice were stimulated with CpG, Curdlan or TDB, an analogon to the mycobacterial cord factor TDM for 48h, respectively. Keywords: card9 knockout, macropphage, TDB

2009-02-01 | GSE10530 | GEO

Card9 dependent activation of macrophages by TDB

2009-01-31 | E-GEOD-10530 | biostudies-arrayexpress

Combined phosphoproteome and transcriptome analysis of the macrophage response to mycobacterial cord factor reveals a dichotomy of MINCLE-dependent and -independent signaling

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

RNAseq analysis of resting and TDM-stimulated DGCR8-deficient macrophages

Project description:Pathogenic mycobacteria subvert immune responses to survive and replicate in macrophages. Mycobacterial cell wall components are sensed by several C-type lectin receptors, including MINCLE, the receptor for the cord factor trehalose-6,6-dimycolate (TDM). Regulation of innate immune cells relies on miRNAs, some of which are induced by mycobacterial ligands. Thus, MTB may exploit host miRNAs to establish its niche in macrophages. Here, we have employed conditional knockout mice for the microprocessor component DGCR8 to investigate the impact of miRNAs on the macrophage response to the mycobacterial cord factor. Deletion of DGCR8 during differentiation of macrophages from bone marrow progenitors significantly reduced the cell yield, but did not interfere with macrophage differentiation as determined by typical surface marker expression and phagocytic capacity. DGCR8-deficient macrophages expressed reduced levels of constitutive and TDM-inducible miRNAs, yet in turn accumulated primary miRNA transcripts. RNAseq revealed a modest type I interferon (IFN) signature in resting DGCR8-deficient macrophages. Stimulation of DGCR8-deficient macrophages with TDM induced overshooting and prolonged expression of interferon response genes, which was associated with enhanced expression of IFNb and could be largely prevented by antibodies to type I interferon. In turn, exogenous IFNb upregulated CXCL10 and CD69 to similar levels in control and DGCR8-deficient macrophages, indicating that signaling downstream of the type I IFN receptor was unaltered. Infection with live Mycobacterium bovis Bacille Calmette-Guerin (BCG) replicated the enhanced interferon response of DGCR8-deficient macrophages. Together, our results reveal an essential role for DGCR8 in curbing IFNb expression and IFN-dependent macrophage activation by mycobacteria.

2020-04-28 | GSE149441 | GEO

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2009-02-01 | GSE10532 | GEO

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Project description:Bone marrow derived macrophages 1 ÂµM CpG or 20 Âµg/ml TDB, an analogon to the mycobacterial cord factor TDM for 8h, 24h, 48h and 72h respectively. Experiment Overall Design: time series; 8h, 24h, 48h and 72h CpG or TDB

2009-02-08 | E-GEOD-10532 | biostudies-arrayexpress

Mycobacterial TDM Reprograms Macrophage Global Gene Expression

Project description:Effect of mycobacterial cell wall component TDM (trehalose dimycolate) of murine macrophage gene expression.

2013-03-09 | E-MEXP-3814 | biostudies-arrayexpress

Expression data from peritoneal macrophages stimulated with trehalose-6,6'-dimycolate (TDM)

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Expression data from peritoneal macrophages stimulated with trehalose-6,6'-dimycolate (TDM)

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