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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| Hauptverfasser: | , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
15 Sep 2020
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| In: |
The journal of immunology
Year: 2020, Jahrgang: 205, Heft: 6, Pages: 1580-1592 |
| ISSN: | 1550-6606 |
| DOI: | 10.4049/jimmunol.2000337 |
| Online-Zugang: | 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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| Verfasserangaben: | 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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| 245 | 1 | 0 | |a Mycobacterial cord factor reprograms the macrophage response to IFN-γ towards enhanced inflammation yet impaired antigen presentation and expression of GBP1 |c 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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| 520 | |a 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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