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.
Visual Abstract
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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