Mycobacterial Cord Factor Reprograms the Macrophage Response to IFN-γ towards Enhanced Inflammation yet Impaired Antigen Presentation and Expression of GBP1

Huber A, Killy B, Grummel N, Bodendorfer B, Paul S, Wiesmann V, Naschberger E, Zimmer J, Wirtz S, Schleicher U, Vera J, Ekici AB, Dalpke A, Lang R (2020)

Publication Type: Journal article, Original article

Publication year: 2020

Journal

Journal of Immunology American Association of Immunologists

Book Volume: 205

Pages Range: 1580-1592

Journal Issue: 6

DOI: 10.4049/jimmunol.2000337

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.

Authors with CRIS profile

Barbara Killy Professur für Mikrobiologie Nadine Grummel Sonderforschungsbereich/Transregio 225/2: Von den Grundlagen der Biofabrikation zu funktionalen Gewebemodellen Elisabeth Naschberger Medizinische Fakultät Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Ulrike Schleicher Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Julio Vera González Professur für Tumorimmunologie (Schwerpunkt Systembiologie) Arif Bülent Ekici Lehrstuhl für Humangenetik Roland Lang Professur für Angeborene Immunität und Pathogenerkennung

Involved external institutions

Universitätsklinikum Heidelberg DE Germany (DE) Fraunhofer-Institut für Integrierte Systeme und Bauelementetechnologie (IISB) DE Germany (DE)

How to cite

APA:

Huber, A., Killy, B., Grummel, N., Bodendorfer, B., Paul, S., Wiesmann, V.,... Lang, R. (2020). Mycobacterial Cord Factor Reprograms the Macrophage Response to IFN-γ towards Enhanced Inflammation yet Impaired Antigen Presentation and Expression of GBP1. Journal of Immunology, 205(6), 1580-1592. https://doi.org/10.4049/jimmunol.2000337

MLA:

Huber, Alexandra, et al. "Mycobacterial Cord Factor Reprograms the Macrophage Response to IFN-γ towards Enhanced Inflammation yet Impaired Antigen Presentation and Expression of GBP1." Journal of Immunology 205.6 (2020): 1580-1592.

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