Cystathionine-γ-lyase ameliorates the histone demethylase JMJD3-mediated autoimmune response in rheumatoid arthritis

Cystathionine-γ-lyase(CSE),an enzyme associated with hydrogen sulfide(H2S)production,is an important endogenous regulator of inflammation.Jumonji domain-containing protein 3(JMJD3)is implicated in the immune response and inflammation.Here,we investigated the potential contribution of JMJD3 to endogenous CSE-mediated inflammation in rheumatoid arthritis(RA).Upregulated CSE and JMJD3 were identified in synovial fibroblasts(SFs)from RA patients as well as in the joints of arthritic mice.Knocking down CSE augmented inflammation in IL-1β-induced SFs by increasing JMJD3 expression.In addition,CSE−/−mice with collagen-induced arthritis(CIA)developed severe joint inflammation and bone erosion.Conversely,overexpressing CSE inhibited JMJD3 expression by the transcription factor Sp-1 and was accompanied by reduced inflammation in IL-1β-treated SFs.Furthermore,JMJD3 silencing or the administration of the JMJD3 inhibitor GSK-J4 significantly decreased the inflammatory response in IL-1β-treated SFs,mainly by controlling the methylation status of H3K27me3 at the promoter of its target genes.GSK-J4 markedly attenuated the severity of arthritis in CIA mice.In conclusion,suppressing JMJD3 expression by the transcription factor Sp-1 is likely responsible for the ability of CSE to negatively modulate the inflammatory response and reduce the progression of RA.