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Mycobacterial cord factor reprograms the macrophage response to IFN-γ towards enhanced inflammation yet impaired antigen presentation and expression of GBP1

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-ind...

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Main Authors: Huber, Alexandra (Author) , Killy, Barbara (Author) , Grummel, Nadine (Author) , Bodendorfer, Barbara (Author) , Paul, Sushmita (Author) , Wiesmann, Veit (Author) , Naschberger, Elisabeth (Author) , Zimmer, Jana (Author) , Wirtz, Stefan (Author) , Schleicher, Ulrike (Author) , Vera, Julio (Author) , Ekici, Arif Bülent (Author) , Dalpke, Alexander (Author) , Lang, Roland (Author)
Format: Article (Journal)
Language:English
Published: 15 Sep 2020
In: The journal of immunology
Year: 2020, Volume: 205, Issue: 6, Pages: 1580-1592
ISSN:1550-6606
DOI:10.4049/jimmunol.2000337
Online Access:Verlag, Volltext: https://doi.org/10.4049/jimmunol.2000337
Verlag, Volltext: https://www.jimmunol.org/content/early/2020/08/11/jimmunol.2000337
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Author Notes:Alexandra Huber, Barbara Killy, Nadine Grummel, Barbara Bodendorfer, Sushmita Paul, Veit Wiesmann, Elisabeth Naschberger, Jana Zimmer, Stefan Wirtz, Ulrike Schleicher, Julio Vera, Arif Bülent Ekici, Alexander Dalpke, Roland Lang
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Summary: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.
Item Description:Gesehen am 01.12.2020
Physical Description:Online Resource
ISSN:1550-6606
DOI:10.4049/jimmunol.2000337

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