PT  - JOURNAL ARTICLE
AU  - Huber, Alexandra
AU  - Killy, Barbara
AU  - Grummel, Nadine
AU  - Bodendorfer, Barbara
AU  - Paul, Sushmita
AU  - Wiesmann, Veit
AU  - Naschberger, Elisabeth
AU  - Zimmer, Jana
AU  - Wirtz, Stefan
AU  - Schleicher, Ulrike
AU  - Vera, Julio
AU  - Ekici, Arif Bülent
AU  - Dalpke, Alexander
AU  - Lang, Roland
TI  - Mycobacterial Cord Factor Reprograms the Macrophage Response to IFN-γ towards Enhanced Inflammation yet Impaired Antigen Presentation and Expression of GBP1
AID  - 10.4049/jimmunol.2000337
DP  - 2020 Sep 15
TA  - The Journal of Immunology
PG  - 1580--1592
VI  - 205
IP  - 6
4099  - http://www.jimmunol.org/content/205/6/1580.short
4100  - http://www.jimmunol.org/content/205/6/1580.full
SO  - J. Immunol.2020 Sep 15; 205
AB  - 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.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.