| First Author | Huber A | Year | 2020 |
| Journal | J Immunol | Volume | 205 |
| Issue | 6 | Pages | 1580-1592 |
| PubMed ID | 32796022 | Mgi Jnum | J:301512 |
| Mgi Id | MGI:6502426 | Doi | 10.4049/jimmunol.2000337 |
| Citation | Huber A, et al. (2020) Mycobacterial Cord Factor Reprograms the Macrophage Response to IFN-gamma towards Enhanced Inflammation yet Impaired Antigen Presentation and Expression of GBP1. J Immunol 205(6):1580-1592 |
| abstractText | Mycobacteria survive in macrophages despite triggering pattern recognition receptors and T cell-derived IFN-gamma 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-gamma-induced macrophage activation is not known. In this study, we have investigated the cross-regulation of the mouse macrophage transcriptome by IFN-gamma and by TDM or its synthetic analogue trehalose-6,6-dibehenate (TDB). As expected, IFN-gamma 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-gamma. The glycolipids enhanced expression of a subset of IFN-gamma-induced genes associated with inflammation. In contrast, TDM/TDB exerted delayed inhibition of IFN-gamma-induced genes, including pattern recognition receptors, MHC class II genes, and IFN-gamma-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-gamma-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-gamma-induced Ag presentation and antimicrobial gene expression by the mycobacterial cord factor that may contribute to mycobacterial persistence. |
