Mycobacterial Cord Factor Reprograms the Macrophage Response to IFN-γ towards Enhanced Inflammation yet Impaired Antigen Presentation and Expression of GBP1.
J Immunol
; 205(6): 1580-1592, 2020 09 15.
Article
em En
| MEDLINE
| ID: mdl-32796022
ABSTRACT
Mycobacteria survive in macrophages despite triggering pattern recognition receptors and T cell-derived IFN-γ production. Mycobacterial cord factor trehalose-6,6-dimycolate (TDM) binds the C-type lectin receptor MINCLE and induces inflammatory gene expression. However, the impact of TDM on IFN-γ-induced macrophage activation is not known. In this study, we have investigated the cross-regulation of the mouse macrophage transcriptome by IFN-γ and by TDM or its synthetic analogue trehalose-6,6-dibehenate (TDB). As expected, IFN-γ induced genes involved in Ag presentation and antimicrobial defense. Transcriptional programs induced by TDM and TDB were highly similar but clearly distinct from the response to IFN-γ. The glycolipids enhanced expression of a subset of IFN-γ-induced genes associated with inflammation. In contrast, TDM/TDB exerted delayed inhibition of IFN-γ-induced genes, including pattern recognition receptors, MHC class II genes, and IFN-γ-induced GTPases, with antimicrobial function. TDM downregulated MHC class II cell surface expression and impaired T cell activation by peptide-pulsed macrophages. Inhibition of the IFN-γ-induced GTPase GBP1 occurred at the level of transcription by a partially MINCLE-dependent mechanism that may target IRF1 activity. Although activation of STAT1 was unaltered, deletion of Socs1 relieved inhibition of GBP1 expression by TDM. Nonnuclear Socs1 was sufficient for inhibition, suggesting a noncanonical, cytoplasmic mechanism. Taken together, unbiased analysis of transcriptional reprogramming revealed a significant degree of negative regulation of IFN-γ-induced Ag presentation and antimicrobial gene expression by the mycobacterial cord factor that may contribute to mycobacterial persistence.
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Base de dados:
MEDLINE
Assunto principal:
Tuberculose
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Proteínas de Ligação ao GTP
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Fatores Corda
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Lectinas Tipo C
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Inflamação
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Macrófagos
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Proteínas de Membrana
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Mycobacterium tuberculosis
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article