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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

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 and Roland Lang
J Immunol September 15, 2020, 205 (6) 1580-1592; DOI: https://doi.org/10.4049/jimmunol.2000337
Alexandra Huber
*Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany;
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Barbara Killy
*Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany;
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Nadine Grummel
*Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany;
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Barbara Bodendorfer
*Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany;
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Sushmita Paul
†Laboratory of Systems Tumor Immunology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany;
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Veit Wiesmann
‡Fraunhofer-Institut für Integrierte Schaltungen, D-91058 Erlangen, Germany;
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Elisabeth Naschberger
§Molekulare und Experimentelle Chirurgie, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nuremberg, D-91054 Erlangen, Germany;
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Jana Zimmer
¶Department of Infectious Diseases, University Hospital Heidelberg, D-69120 Heidelberg, Germany;
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Stefan Wirtz
‖Medizinische Klinik 1, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany;
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Ulrike Schleicher
*Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany;
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Julio Vera
†Laboratory of Systems Tumor Immunology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany;
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Arif Bülent Ekici
#Institut für Humangenetik, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany; and
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Alexander Dalpke
¶Department of Infectious Diseases, University Hospital Heidelberg, D-69120 Heidelberg, Germany;
**Institut für Medizinische Mikrobiologie und Hygiene, Technische Universität Dresden, 01307 Dresden, Germany
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Roland Lang
*Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany;
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Key Points

  • TDM has an ambiguous impact on the macrophage response to IFN-γ.

  • TDM impairs IFN-γ–induced Ag presentation via MHC-II and GBP1 expression.

  • Inhibition by TDM does not affect STAT1 phosphorylation, but requires SOCS1.

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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.

Footnotes

  • This work was supported by grants from the Deutsche Forschungsgemeinschaft to R.L. (SFB 796 TP B06 and SFB 1181 TP A06).

  • The microarray dataset presented in this article has been submitted to Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE137150.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    BMM
    bone marrow–derived macrophage
    cDMEM
    complete DMEM
    CLR
    C-type lectin receptor
    CT
    threshold cycle
    DC
    dendritic cell
    Gbp
    GTPase-binding protein
    GO
    Gene Ontology
    IRF1
    IFN regulatory factor 1
    KO
    knockout
    MHC-II
    MHC class II
    PAMP
    pathogen-associated molecular pattern
    qRT-PCR
    quantitative real-time PCR
    RT
    room temperature
    SOCS1
    suppressor of cytokine signaling 1
    SOCS1ΔNLS
    nonnuclear SOCS1
    SYK
    spleen tyrosine kinase
    TDB
    trehalose-6,6-dibehenate
    TDM
    trehalose-6,6-dimycolate
    TFBS
    transcription factor binding site
    WT
    wild-type.

  • Received March 26, 2020.
  • Accepted July 9, 2020.
  • Copyright © 2020 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 205 (6)
The Journal of Immunology
Vol. 205, Issue 6
15 Sep 2020
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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
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
The Journal of Immunology September 15, 2020, 205 (6) 1580-1592; DOI: 10.4049/jimmunol.2000337

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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
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
The Journal of Immunology September 15, 2020, 205 (6) 1580-1592; DOI: 10.4049/jimmunol.2000337
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