Epigenetic changes in inflammatory arthritis monocytes contribute to disease and can be targeted by JAK inhibition

Objectives How the local inflammatory environment regulates epigenetic changes in the context of inflammatory arthritis remains unclear. Here we assessed the transcriptional and active enhancer profile of monocytes derived from the inflamed joints of Juvenile Idiopathic Arthritis (JIA) patients, a model well-suited for studying inflammatory arthritis.
Methods RNA-sequencing and H3K27me3 chromatin immunoprecipitation sequencing (ChIP-seq) were used to analyze the transcriptional and epigenetic profile, respectively, of JIA synovial fluid-derived monocytes.
Results Synovial-derived monocytes display an activated phenotype, which is regulated on the epigenetic level. IFN signaling-associated genes are increased and epigenetically altered in synovial monocytes, indicating a driving role for IFN in establishing the local inflammatory phenotype. Treatment of synovial monocytes with the Janus-associated kinase (JAK) inhibitor ruxolitinib, which inhibits IFN signaling, transformed the activated enhancer landscape and reduced disease-associated gene expression, thereby inhibiting the inflammatory phenotype.
Conclusion This study provides novel insights into epigenetic regulation of inflammatory arthritis patient-derived monocytes and highlights the therapeutic potential of epigenetic modulation for the treatment of inflammatory rheumatic diseases.

Data deposited

H3K27ac ChIP-seq peak coordinates of healthy control peripheral blood-derived monocytes and JIA peripheral blood- and synovial fluid-derived monocytes (Figure 2 in article).

Individual and merged peak coordinates of H3K27ac and H3K4me1 ChIP-seq on JIA monocytes with and without Ruxolitinib and IFN gamma (Figure 4 in article).

Gene expression data of JIA monocytes treated with and without JQ1 (Figure 2 in article).

Gene expression data of Ruxolitinib- and IFN-stimulated JIA monocytes (Figure 5 in article).