Chen Chun-Yu, Yang Chuan-Hui, Tsai Yung-Fong, Liaw Chih-Chuang, Chang Wen-Yi, Hwang Tsong-Long
Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
Redox Biol. 2017 Apr;11:263-274. doi: 10.1016/j.redox.2016.12.018. Epub 2016 Dec 18.
The NOD-like receptor pyrin domain 3 (NLRP3) inflammasome contains Nod-like receptors, a subclass of pattern recognition receptors, suggesting that this complex has a prominent role in host defenses. Various structurally diverse stimulators activate the NLRP3 inflammasome through different signaling pathways. We previously reported that ugonin U (UgU), a natural flavonoid isolated from Helminthostachys zeylanica (L) Hook, directly stimulates phospholipase C (PLC) and triggers superoxide release in human neutrophils. In the present study, we showed that UgU induced NLRP3 inflammasome assembly and subsequent caspase-1 and interleukin (IL)-1β processing in lipopolysaccharide-primed human monocytes. Moreover, UgU elicited mitochondrial superoxide generation in a dose-dependent manner, and a specific scavenger of mitochondrial reactive oxygen species (ROS) diminished UgU-induced IL-1β and caspase-1 activation. UgU induced Ca mobilization, which was inhibited by treatment with inhibitors of PLC or inositol triphosphate receptor (IPR). Blocking Ca mobilization, PLC, or IPR diminished UgU-induced IL-1β release, caspase-1 activation, and mitochondrial ROS generation. These data demonstrated that UgU activated the NLPR3 inflammasome activation through Ca mobilization and the production of mitochondrial ROS. We also demonstrated that UgU-dependent NLRP3 inflammasome activation enhanced the bactericidal function of human monocytes. The ability of UgU to stimulate human neutrophils and monocytes, both of which are professional phagocytes, and its capacity to activate the NLRP3 inflammasome, which is a promising molecular target for developing anti-infective medicine, indicate that UgU treatment should be considered as a possible novel therapy for treating infectious diseases.
NOD样受体含pyrin结构域3（NLRP3）炎性小体包含Nod样受体，它是模式识别受体的一个亚类，这表明该复合物在宿主防御中具有重要作用。各种结构多样的刺激物通过不同的信号通路激活NLRP3炎性小体。我们之前报道过，从七指蕨中分离出的天然黄酮类化合物乌冈栎素U（UgU）可直接刺激磷脂酶C（PLC）并触发人中性粒细胞释放超氧化物。在本研究中，我们发现UgU可诱导脂多糖预处理的人单核细胞中NLRP3炎性小体组装以及随后的半胱天冬酶-1（caspase-1）和白细胞介素（IL）-1β的加工处理。此外，UgU以剂量依赖性方式引发线粒体超氧化物生成，并且线粒体活性氧（ROS）的特异性清除剂可减少UgU诱导的IL-1β和caspase-1激活。UgU诱导钙动员，这可被PLC或肌醇三磷酸受体（IPR）抑制剂处理所抑制。阻断钙动员、PLC或IPR可减少UgU诱导的IL-1β释放、caspase-1激活和线粒体ROS生成。这些数据表明，UgU通过钙动员和线粒体ROS生成激活NLRP3炎性小体。我们还证明，UgU依赖的NLRP3炎性小体激活增强了人单核细胞的杀菌功能。UgU刺激人中性粒细胞和单核细胞（二者均为专业吞噬细胞）的能力，以及其激活NLRP3炎性小体的能力（NLRP3炎性小体是开发抗感染药物的一个有前景的分子靶点）表明，UgU治疗应被视为治疗传染病的一种可能的新疗法。
