Novel pharmacological inhibition of EZH2 attenuates septic shock by altering innate inflammatory responses to sepsis

Lunxian Tang
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引用次数: 1

Abstract

The function of histone methyltransferase enhancer of zeste homolog 2 (EZH2) in sepsis remains unknown. We reported here that the expression of EZH2 and H3K27me3 was significantly upregulated in the circulation of septic patients, whereas patients who survived presented downregulated the expression of EZH2 on CD14+ monocytes/macrophages. We further identified increased expression of EZH2 in the circulation, peritoneal fluid, and septic lungs from CLP mice. 3-DZNeP treated CLP mice improved mortality and protected from organ injury. EZH2 inhibition not only suppressed the activation of inflammatory cells and release of cytokines in the circulation and infectious sites, but also promoted bacteria clearance and replenished the circulating monocyte and neutrophil pool from bone marrow. Blockage of EZH2 also suppressed the progression of lung injury and alleviated inflammation by decreasing the pulmonary cell apoptosis, reducing inflammatory cells infiltration and cytokines release through inhibition of the STAT3 signaling pathway and recovery of PPARγ activation. In addition, EZH2 inhibitor blunted macrophage M1 polarization by SOCS3/STAT1 pathway. Overall, these data suggest that EZH2 could be a potential biomarker predicting clinical outcome and a new target for therapeutic interference in sepsis.
新型药物抑制EZH2通过改变先天炎症反应来减轻脓毒症休克
zeste同源物2组蛋白甲基转移酶增强子(EZH2)在脓毒症中的作用尚不清楚。我们在这里报道了脓毒症患者循环中EZH2和H3K27me3的表达显著上调,而存活的患者CD14+单核/巨噬细胞中EZH2的表达下调。我们进一步发现EZH2在CLP小鼠的循环、腹膜液和脓毒性肺中的表达增加。3-DZNeP治疗CLP小鼠可改善死亡率并保护其免受器官损伤。EZH2抑制不仅抑制了循环和感染部位炎症细胞的激活和细胞因子的释放,而且促进了细菌的清除,补充了骨髓循环中的单核细胞和中性粒细胞池。阻断EZH2还可通过抑制STAT3信号通路,恢复PPARγ激活,减少肺细胞凋亡,减少炎症细胞浸润和细胞因子释放,从而抑制肺损伤进展,减轻炎症。此外,EZH2抑制剂通过SOCS3/STAT1通路钝化巨噬细胞M1极化。总之,这些数据表明EZH2可能是预测临床结果的潜在生物标志物和脓毒症治疗干预的新靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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