Background/Purpose: To explore the role of EZH2, a histone methylation regulator, in the pathogenesis of rheumatoid arthritis (RA).

Methods: Forty treatment-naïve patients with active disease and fulfilled the 2010 ACR revised criteria for RA were enrolled in the study.

The expression of EZH2 was further quantified by qPCR, WB, and flow cytometry in T cells. The ability of differentiation, proliferation, and apoptosis of T cells was measured by flow cytometry and qPCR after inhibition of EZH2 through pharmacological inhibitor and siRNA. mTOR signaling pathways were also monitored. The effect of synovial fluid and fibroblast-like synoviocyte (FLS) on EZH2 expression in T cell was determined by flow cytometry and qPCR.

Results: EZH2 expression is lower in PBMC and CD4 + T cells from RA patients. EZH2 inhibition with GSK126 or siRNA ex vivo attenuated the differentiation of naïve T cells into regulatory T cells (Treg). Phenotypically, RA showed decreased Treg frequency in peripheral blood. EZH2 silencing could downregulate SMAD3/4 and increased mTOR expression in vitro. Synovial fluid and FLS from RA patients suppress EZH2 expression in T cells.

Conclusion: Lower expression of EZH2 contributed to decreased Treg differentiation in the CD4+ T cells of RA patients, involved in TGF-β/SMAD signaling and mTOR signaling. The synovial fluid and FLS from RA patients played and role in the reduction of EZH2 expression. Targeting EZH2 might be a potential approach for RA treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/defective-ezh2-expression-attenuates-treg-differentiation-in-rheumatoid-arthritis/