IRF8
关节炎
炎性关节炎
表观遗传学
炎症
IRF7
癸他滨
DNA甲基化
FOXP3型
生物
遗传学
免疫学
免疫系统
癌症研究
医学
转录因子
先天免疫系统
基因
基因表达
作者
Gaurav Swarnkar,Nicholas P. Semenkovich,Manoj Arra,D. Mims,Syeda Kanwal Naqvi,Timothy E. Peterson,Gabriel Mbalaviele,Chia‐Lung Wu,Yousef Abu‐Amer
标识
DOI:10.1073/pnas.2310264121
摘要
Epigenetic regulation plays a crucial role in the pathogenesis of autoimmune diseases such as inflammatory arthritis. DNA hypomethylating agents, such as decitabine (DAC), have been shown to dampen inflammation and restore immune homeostasis. In the present study, we demonstrate that DAC elicits potent anti-inflammatory effects and attenuates disease symptoms in several animal models of arthritis. Transcriptomic and epigenomic profiling show that DAC-mediated hypomethylation regulates a wide range of cell types in arthritis, altering the differentiation trajectories of anti-inflammatory macrophage populations, regulatory T cells, and tissue-protective synovial fibroblasts (SFs). Mechanistically, DAC-mediated demethylation of intragenic 5'-Cytosine phosphate Guanine-3' (CpG) islands of the transcription factor Irf8 (interferon regulatory factor 8) induced its re-expression and promoted its repressor activity. As a result, DAC restored joint homeostasis by resetting the transcriptomic signature of negative regulators of inflammation in synovial macrophages (MerTK, Trem2, and Cx3cr1), TREGs (Foxp3), and SFs (Pdpn and Fapα). In conclusion, we found that Irf8 is necessary for the inhibitory effect of DAC in murine arthritis and that direct expression of Irf8 is sufficient to significantly mitigate arthritis.
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