Liu Hongbin, Zhan Xiaoyan, Xu Guang, Wang Zhilei, Li Ruisheng, Wang Yan, Qin Qin, Shi Wei, Hou Xiaorong, Yang Ruichuang, Wang Jian, Xiao Xiaohe, Bai Zhaofang
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China; Department of Pharmacy, Hebei North University, Zhangjiakou, 075000, China.
China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China.
Pharmacol Res. 2021 Feb;164:105384. doi: 10.1016/j.phrs.2020.105384. Epub 2020 Dec 19.
NLRP3 inflammasome activation is implicated in the pathogenesis of a wide range of inflammatory diseases, but medications targeting the NLRP3 inflammasome are not available for clinical use. Here, we demonstrate that cryptotanshinone (CTS), a major component derived from the traditional medicinal herb Salvia miltiorrhiza Bunge, is a specific inhibitor for the NLRP3 inflammasome. Cryptotanshinone inhibits NLRP3 inflammasome activation in macrophages, but has no effects on AIM2 or NLRC4 inflammasome activation. Mechanistically, cryptotanshinone blocks Ca signaling and the induction of mitochondrial reactive oxygen species (mtROS), which are important upstream signals of NLRP3 inflammasome activation. In vivo, cryptotanshinone attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3 inflammasome-mediated diseases such as endotoxemia syndrome and methionine- and choline-deficient-diet-induced nonalcoholic steatohepatitis (NASH). Our findings suggest that cryptotanshinone may be a promising therapeutic agent for the treatment of NLRP3 inflammasome-mediated diseases.
NLRP3炎性小体激活与多种炎症性疾病的发病机制有关，但针对NLRP3炎性小体的药物尚未用于临床。在此，我们证明隐丹参酮（CTS）是传统草药丹参中的一种主要成分，是NLRP3炎性小体的特异性抑制剂。隐丹参酮可抑制巨噬细胞中NLRP3炎性小体的激活，但对AIM2或NLRC4炎性小体的激活没有影响。从机制上讲，隐丹参酮可阻断钙信号传导以及线粒体活性氧（mtROS）的诱导，而这两者是NLRP3炎性小体激活的重要上游信号。在体内，隐丹参酮可减轻NLRP3炎性小体介导的疾病（如内毒素血症综合征和蛋氨酸及胆碱缺乏饮食诱导的非酒精性脂肪性肝炎（NASH））小鼠模型中的半胱天冬酶-1激活和IL-1β分泌。我们的研究结果表明，隐丹参酮可能是治疗NLRP3炎性小体介导疾病的一种有前景的治疗药物。
