Zoledronic acid regulates the synthesis and secretion of IL-1 beta through Histone methylation in macrophages
Zoledronic acid regulates the synthesis and secretion of IL-1 beta through Histone methylation in macrophages
复制标题
唑来膦酸通过巨噬细胞中组蛋白甲基化调节 IL-1β 的合成和分泌
DOI：
10.1038/s41420-020-0273-4
复制
发表时间：
2020
影响因子：
7
通讯作者：
Pan Jinsong
中科院分区：
文献类型：
--
作者：
Yang Xiaojie;Xu Xing;Chen Jun;Wang Qing;Wang Guangfei;Ai Xuemin;Wang Xu;Pan Jinsong
长期服用含氮双膦酸盐会增加有害副作用的风险，如双膦酸盐相关的颌骨骨坏死（BRONJ）。BRONJ的发展与炎症有关，但其病理生理机制尚不清楚。在这里，我们研究了组蛋白甲基化是否与唑来膦酸（Zol）诱导的炎症反应有关。我们发现Kdm6a和Kdm6b显著增加了巨噬细胞中被Caspase 1激活的白介素1β的表达和Gasdermin D的裂解。Kdm6a和Kdm6b抑制剂可有效抑制zol增强的巨噬细胞中白细胞介素1β的合成和分泌。当Kdm6a和Kdm6b在体内被药理学抑制时，zol处理小鼠的牙槽窝愈合不良和炎症反应得到改善。综上所述，我们展示了Kdm6a和Kdm6b在zol促进的炎症反应中的病理作用，并证明了Kdm6a和Kdm6b是治疗BRONJ的潜在治疗靶点。
Long-term administration of nitrogen-containing bisphosphonates increases the risk of detrimental side effects, such as bisphosphonate-related osteonecrosis of the jaw (BRONJ). BRONJ development is associated with inflammation, but its pathophysiology remains unknown. Here, we examined whether histone methylation is responsible for zoledronic acid (Zol)-induced inflammatory responses. We found that Kdm6a and Kdm6b markedly increased interleukin 1β expression and Gasdermin D cleavage, which are both activated by Caspase 1, in macrophages. Inhibitors of Kdm6a and Kdm6b robustly abolished Zol-enhanced interleukin 1β synthesis and secretion from macrophages. When Kdm6a and Kdm6b were pharmacologically inhibited in vivo, poor healing of the alveolar socket and inflammatory responses were ameliorated in Zol-treated mice. Taken together, we showed the pathologic role of Kdm6a and Kdm6b in Zol-promoted inflammatory responses and demonstrated that Kdm6a and Kdm6b are potential therapeutic targets for the treatment of BRONJ.