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Abstract：
Aberrant activation of NLRP3 inflammasome in colonic macrophages strongly associates with the occurrence and progression of ulcerative colitis. Although targeting NLRP3 inflammasome has been considered to be a potential therapy, the underlying mechanism through which pathway the intestinal inflammation is modulated remains controversial. By focusing on the flavonoid lonicerin, one of the most abundant constituents existed in a long historical anti-inflammatory and anti-infectious herb Lonicera japonica Thunb., here we report its therapeutic effect on intestinal inflammation by binding directly to enhancer of zeste homolog 2 (EZH2) histone methyltransferase. EZH2-mediated modification of H3K27me3 promotes the expression of autophagy-related protein 5, which in turn leads to enhanced autophagy and accelerates autolysosome-mediated NLRP3 degradation. Mutations of EZH2 residues (His129 and Arg685) indicated by the dynamic simulation study have found to greatly diminish the protective effect of lonicerin. More importantly, in vivo studies verify that lonicerin dose-dependently disrupts the NLRP3-ASC-pro-caspase-1 complex assembly and alleviates colitis, which is compromised by administration of EZH2 overexpression plasmid. Thus, these findings together put forth the stage for further considering lonicerin as an anti-inflammatory epigenetic agent and suggesting EZH2/ATG5/NLRP3 axis may serve as a novel strategy to prevent ulcerative colitis as well as other inflammatory diseases.
摘要：
结肠巨噬细胞中NLRP3炎性体的异常激活与溃疡性结肠炎的发生和进展密切相关。尽管靶向NLRP3炎性体被认为是一种潜在的治疗方法，肠道炎症的调节途径的潜在机制仍存在争议。通过关注黄酮类金银花，在历史悠久的抗炎和抗感染中药金银花中存在最丰富的成分之一。,在这里，我们报告了其通过直接结合zeste同源物2（EZH2）组蛋白甲基转移酶的增强剂对肠道炎症的治疗作用。EZH2介导的H3K27me3修饰促进自噬相关蛋白5的表达，进而导致自噬增强并加速自溶体介导的NLRP3降解。动态模拟研究表明，EZH2残基（His129和Arg685）的突变会大大降低金银花的保护作用。更重要的是,体内研究证实金丝雀素剂量依赖性地破坏NLRP3-ASC-pro-caspase-1复合物组装并缓解结肠炎，其通过施用EZH2过表达质粒而受损。因此，这些发现共同提出了进一步考虑金银花素作为抗炎表观遗传因子的阶段,并提示EZH2/ATG5/NLRP3轴可作为预防溃疡性结肠炎及其他炎症性疾病的新策略.
