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

• Verfasst von: Huber, Alexandra [VerfasserIn]
• Verfasst von: Killy, Barbara [VerfasserIn]
• Verfasst von: Grummel, Nadine [VerfasserIn]
• Verfasst von: Bodendorfer, Barbara [VerfasserIn]
• Verfasst von: Paul, Sushmita [VerfasserIn]
• Verfasst von: Wiesmann, Veit [VerfasserIn]
• Verfasst von: Naschberger, Elisabeth [VerfasserIn]
• Verfasst von: Zimmer, Jana [VerfasserIn]
• Verfasst von: Wirtz, Stefan [VerfasserIn]
• Verfasst von: Schleicher, Ulrike [VerfasserIn]
• Verfasst von: Vera, Julio [VerfasserIn]
• Verfasst von: Ekici, Arif Bülent [VerfasserIn]
• Verfasst von: Dalpke, Alexander [VerfasserIn]
• Verfasst von: Lang, Roland [VerfasserIn]
• Titel: Mycobacterial cord factor reprograms the macrophage response to IFN-γ towards enhanced inflammation yet impaired antigen presentation and expression of GBP1
• Verf.angabe: 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
• E-Jahr: 2020
• Jahr: 15 Sep 2020
• Umfang: 13 S.
• Teil: volume:205
• Teil: year:2020
• Teil: number:6
• Teil: pages:1580-1592
• Teil: extent:13
• Fussnoten: Gesehen am 01.12.2020
• Titel Quelle: Enthalten in: The journal of immunology
• Ort Quelle: Bethesda, Md. : Soc., 1916
• Jahr Quelle: 2020
• Band/Heft Quelle: 205(2020), 6, Seite 1580-1592
• ISSN Quelle: 1550-6606
• DOI: doi:10.4049/jimmunol.2000337
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1741631408

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.