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Transcriptional and translational analysis of wild-type and Mincle-KO macrophages

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE70793 | GEO | 2016/07/10

SECONDARY ACCESSION(S): PRJNA289540

REPOSITORIES: GEO

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Role of Mincle overexpression in pneumococcal pneumonia

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.

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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

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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.

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2013-11-14 | E-GEOD-52338 | biostudies-arrayexpress

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

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