Targeting histone acetylation enables epigenetic modulation of inflammatory pathways, a novel therapeutic strategy for rheumatoid arthritis

Abstract

Autoimmune diseases like rheumatoid arthritis (RA) are characterized by a systemic inflammation caused by autoreactive immune cells. Epigenomic modulation of these cells offers a strategy to reprogram pathogenic pathways without altering the genome, potentially restoring immune balance. Epigenetic inhibitors are already utilized in oncology but often exhibit adverse effects due to lack of selectivity and cytotoxic concentrations. Applying these drugs to treat autoimmune diseases necessitates more selective inhibitors and the use of tolerable concentrations. In this study, we screened a library of 25 compounds with varying degrees of target selectivity and different concentrations. Spectral cytometry enabled the analysis of cell-subset distribution and activation, followed by bulk RNA-sequencing for transcriptomic profiling. We could demonstrate cell-subset specific and concentration-dependent immune modulation in PBMCs. Transcriptomic analysis showed that inhibitors of histone acetylation-modulating enzymes significantly altered gene expression, particularly in immune regulation pathways relevant to autoimmune diseases. Comparative analysis between in-vitro treated healthy controls and RA patients demonstrated both shared and selective drug effects, with some inhibitors like Ricolinostat overlapping with established RA drug pathways. Our findings highlight the potential of epigenetic inhibitors, especially those targeting histone acetylation, to modulate immune responses in a target-selective manner. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/632975v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@30f4faorg.highwire.dtl.DTLVardef@23578borg.highwire.dtl.DTLVardef@4890ceorg.highwire.dtl.DTLVardef@1acbb5_HPS_FORMAT_FIGEXP M_FIG C_FIG