Coordinated glucocorticoid receptor and MAFB action induces tolerogenesis and epigenome remodeling in dendritic cells

Abstract

Glucocorticoids (GCs) exert potent anti-inflammatory effects in immune cells through the glucocorticoid receptor (GR). Dendritic cells (DCs), central actors for coordinating immune responses, acquire tolerogenic properties in response to GCs. Tolerogenic DCs (tolDCs) have emerged as a potential treatment for various inflammatory diseases. To date, the underlying cell type-specific regulatory mechanisms orchestrating GC-mediated acquisition of immunosuppressive properties remain poorly understood. In this study, we investigated the transcriptomic and epigenomic remodeling associated with differentiation to DCs in the presence of GCs. Our analysis demonstrates a major role of MAFB in this process, in synergy with GR. GR and MAFB both interact with methylcytosine dioxygenase TET2 and bind to genomic loci that undergo specific demethylation in tolDCs. We also show that the role of MAFB is more extensive, binding to thousands of genomic loci in tolDCs. Finally, MAFB knockdown erases the tolerogenic properties of tolDCs and reverts the specific DNA demethylation and gene upregulation. The preeminent role of MAFB is also demonstrated in vivo for myeloid cells from synovium in rheumatoid arthritis following GC treatment. Our results imply that, once directly activated by GR, MAFB plays a critical role in orchestrating the epigenomic and transcriptomic remodeling that define the tolerogenic phenotype.

Methylome and transcriptome profiling of giant cell arteritis monocytes reveals novel pathways involved in disease pathogenesis and molecular response to glucocorticoids

“…First, the comparison of the DNA methylation landscape of CD14+ monocytes between patients with GCA and controls unveiled the existence of 1371 differentially methylated positions (DMPs), annotated to 1190 unique genes, across the whole genome (figure 1A). Most DMPs were located in intergenic regions (31.8% hypermethylated and 26.6% hypomethylated) and gene bodies (44.3% hypermethylated and 41.4% hypomethylated) and less frequently in promoters, consistent with the findings of studies in other inflammatory conditions,12 13 which suggests that a substantial part of the methylation aberrations might be located in distal regulatory regions. In addition, DMPs, mainly hypermethylated DMPs, were mostly located in open sea regions, outside CpG island and surrounding areas (figure 1B).…”

“…On another side, treated patients showed downregulation in multiple inflammatory-related pathways, apoptotic processes and, notably, defence response to viruses, including pathways such as Herpes simplex infection, Epstein-Barr virus infection, Hepatitis B and Influenza A, among others (figure 4E and online supplemental table 37). Unlike the similarity observed in DNA methylation patterns, the large differences identified in the gene expression patterns between treated and untreated patients are supported by previous evidence describing, in other immune contexts, that the GC treatment has an important effect in reshaping the gene expression landscape but relatively low impact in the DNA methylation profile 13…”

Vitamin C triggers NF-κB-driven epigenomic reprogramming and enhanced immunogenic responses of dendritic cells

“…The functional relationship between DNA demethylation and gene expression has been extensively studied in several contexts( 7 , 9 , 10 , 12 , 13 ). Genes more expressed in mDC vitC than mDC, from E1 and E2 clusters are enriched in M1-associated genes.…”

“…Recently, TET2 has also been implicated in glucocorticoid-and vitamin D-mediated modulation of the immunogenic properties of DCs (12,13).…”

“…TET2, a member of the Ten-Eleven Translocation (TET) methylcytosine dioxygenases, is involved in multi-step active demethylation processes, and is critical for terminal MO-related differentiation( 6 , 11 ). Recently, TET2 has also been implicated in glucocorticoid- and vitamin D-mediated modulation of the immunogenic properties of DCs( 12 , 13 ).…”