Coordinated glucocorticoid receptor and MAFB action induces tolerogenesis and epigenome remodeling in dendritic cells.
Nucleic Acids Res
; 50(1): 108-126, 2022 01 11.
Article
in En
| MEDLINE
| ID: mdl-34893889
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Dendritic Cells
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Receptors, Glucocorticoid
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Epigenesis, Genetic
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MafB Transcription Factor
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Immune Tolerance
Limits:
Adult
/
Female
/
Humans
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Male
/
Middle aged
Language:
En
Journal:
Nucleic Acids Res
Year:
2022
Document type:
Article
Affiliation country:
España