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

Abstract

Cystathionine-γ-lyase (CSE), an enzyme associated with hydrogen sulfide (HS) 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.

Epigenetics and Vascular Senescence–Potential New Therapeutic Targets?

“…Moreover, deficiency of JMJD3 reduces neointima formation after vascular injury by inhibits the Nox4-autophagy signaling pathway. These observations suggesting that JMJD3 may represent a novel target for the development of new anti-inflammatory therapeutics for treating RA, the prevention and treatment of intima hyperplasia-related vascular diseases, and other pro-inflammatory conditions (Liu et al, 2018;Jia et al, 2018a;Luo et al, 2018;Wu et al, 2019). Likewise, the transcription factor GATA4, a key regulator of angiogenesis and persistence of inflammation in RA may also hold promise as a therapeutic target (Jia et al, 2018).…”

“…Additional research from our group has identified histone demethylase Jumonji domain-containing protein 3 (JMJD3) as a key epigenetic regulator of the inflammatory response in cells (Liu et al, 2018). JMJD3 playing a pivitol role in rheumatoid synovial hyperplasia in rheumatoid arthritis (RA) (Jia et al, 2018a;Wu et al, 2019). Moreover, evidence also points to potential roles for JMJD3 in vascular remodeling (Luo et al, 2018) and in the regulation of the transcription factor GATA4.…”

Epigenetic Regulation Mediated by Methylation in the Pathogenesis and Precision Medicine of Rheumatoid Arthritis

“…The expression of Jumonji domain-containing protein 3 (JMJD3) in RASFs is up-regulate. JMJD3 specifically demethylates trimethylated lysine, which is directly involved in the activation of TLR2 gene through the demethylation of H3K27me3 promoter and promotes RA inflammation (Wu et al, 2019). Aiming at the pathogenesis of RA caused by abnormal histone methylation is helpful to improve the inflammation of RA.…”

“…Aiming at the pathogenesis of RA caused by abnormal histone methylation is helpful to improve the inflammation of RA. For example, the application of JMJD3 inhibitor GSK-J4 inhibits the methylation of H3K27me3 at the TLR2 promoter, significantly relieved the destruction and inflammation of articular cartilage (Wu et al, 2019). Therefore, histone modification regulators are potential and promising drug targets for RA therapy and drug development.…”

Zoledronic acid regulates the synthesis and secretion of IL-1β through Histone methylation in macrophages

“…Sufficient evidence suggests that epigenetic alterations mediate the development of inflammation by regulating inflammatory gene transcription 15 . Histone aminoterminal tails are subject to multiple post-translational modifications, such as phosphorylation, ubiquitination, acetylation and methylation.…”