Background:
There is compelling genetic, laboratory and environmental evidence that vitamin D contributes to MS pathogenesis, but the inactive forms currently used in clinical trials have failed to provide benefit. This is because of genetic and epigenetic bottlenecks to vitamin D response.
Objective:
An improved approach is needed to obtain benefit from the vitamin D pathway. The objective of this study was to define how vitamin D promotes a tolerogenic phenotype in the immunological context most likely to underpin its benefit: control of dendritic cells.
Methods:
We identified how the chromatin is remodelled using ATACseq (Assay for Transposase-Accessible Chromatin using sequencing) and global gene expression changes using RNAseq in response to treatment with calcipotriol (active vitamin D analogue) for monocyte-derived dendritic cells with a tolerogenic or inflammatory phenotype. We also characterised the effect of co-treatment with vitamin D and a novel bromodomain inhibitor, i-BRD9.
Results:
ATACseq revealed distinct chromatin accessibility changes in response to calcipotriol with over 4,000 genomic locations affected, accounting for approximately 8% of the variation in the ATACseq dataset. Transcriptomic analysis also showed a clear vitamin D response signature, with a far larger number of genes dysregulated in response to calcipotriol the inflammatory cells compared to the tolerogenic cells. Pathway analysis indicated a reduced inflammatory state in cells treated with calcipotriol.
Conclusions:
Calcipotriol treatment revealed a distinct a shift away from the inflammatory phenotype to a more immunosuppressive/tolerogenic phenotype. Work is ongoing to assess alternative strategies, including co-treatment with i-BRD9, to upregulate the vitamin D response and bypass the body’s homeostatic setpoint.