目的:我们分析了RNA-SEQ数据,发现干燥综合征(SS)患者唾液腺(SGs)中EZH2基因表达上调,并与病理损伤相关。在这项研究中,我们试图确定抑制EZH2是否会改善NOD/Ltj(NOD)小鼠的SS样疾病。
方法:我们从GEO数据库获得的数据中分析了SS患者SGs的RNA-SEQ数据,以探索EZH2基因表达与SS进展之间的相关性。通过使用预防性和治疗性模型两者腹膜内施用GSK343来实现NOD小鼠中EZH2的抑制。GSK343对SGs分泌和病理损伤的影响,以及T细胞的水平和功能,B细胞,髓源性抑制细胞(MDSCs),和其他免疫细胞进行了评估。
结果:SS患者SGs中编码EZH2的基因表达水平明显高于非SS患者,表达水平与SGs病理损伤的严重程度呈正相关。与对照小鼠相比,GSK343处理显著增加NOD小鼠中SGs的唾液流速和病理损伤。此外,GSK343显著抑制CD4+和CD8+T细胞的数量和促炎因子的分泌,抑制SS引起的Th1/Th2细胞比例的增加。RNA-SEQ数据还显示EZH2在SS的发病机理中抑制几种炎症途径。
结论:SS患者下颌下腺组织中EZH2表达上调。抑制EZH2减轻了NOD小鼠的SS样疾病,提示EZH2可能是临床治疗SS的潜在靶点。
OBJECTIVE: We analyzed RNA-SEQ data and found that EZH2 gene expression in salivary glands (SGs) of Sjögren\'s syndrome (SS) patients was up-regulated and correlated with pathological injury. In this study, we sought to determine if inhibiting EZH2 would ameliorate SS-like disease in NOD/Ltj (NOD) mice.
METHODS: We analyzed RNA-SEQ data of SGs of patients with SS from data obtained from the GEO database to explore the correlation between EZH2 gene expression and the progression of SS. Inhibition of EZH2 in the NOD mice was achieved by intraperitoneal administration of
GSK343 using both a preventative and a therapeutic model. The effects of
GSK343 on SGs secretion and pathological damage, as well as the levels and functions of T cells, B cells, Myeloid-derived suppressor cells (MDSCs), and other immune cells were evaluated.
RESULTS: The expression levels of the gene encoding EZH2 in the SGs of SS patients were significantly higher than the non-SS sicca patients, and the expression levels were positively correlated with the severity of the SGs pathological damage.
GSK343 treatment significantly increased the salivary flow rate and pathological damage of the SGs in the NOD mice compared to the control mice. In addition,
GSK343 significantly inhibited the number and pro-inflammatory-factor secretion of CD4+ and CD8+ T cells and inhibited the increase in the Th1/Th2 cell ratio caused by SS. RNA-SEQ data also showed that EZH2 inhibited several inflammatory pathways during the pathogenesis of SS.
CONCLUSIONS: EZH2 expression was up-regulated in the submandibular gland tissue of SS patients.Inhibition of EZH2 alleviated SS-like disease in NOD mice, suggesting that EZH2 might be a potential target for the clinical treatment of SS.