Zha Qing-Bing, Wei Hong-Xia, Li Chen-Guang, Liang Yi-Dan, Xu Li-Hui, Bai Wen-Jing, Pan Hao, He Xian-Hui, Ouyang Dong-Yun
Department of Fetal Medicine, The First Affiliated Hospital of Jinan University , Guangzhou , China.
Department of Immunobiology, College of Life Science and Technology, Jinan University , Guangzhou , China.
Front Immunol. 2016 Dec 12;7:597. doi: 10.3389/fimmu.2016.00597. eCollection 2016.
Adenosine triphosphate (ATP) is released by bacteria and host cells during bacterial infection as well as sterile tissue injury, acting as an inducer of inflammasome activation. Previous studies have shown that ATP treatment leads to AMP-activated protein kinase (AMPK) activation. However, it is unclear whether AMPK signaling has been involved in the regulation of ATP-induced inflammasome activation and subsequent pyroptosis. In this study, we aimed to investigate this issue in lipopolysaccharide-activated murine macrophages. Our results showed that AMPK signaling was activated in murine macrophages upon ATP treatment, which was accompanied by inflammasome activation and pyroptosis as evidenced by rapid cell membrane rupture as well as mature interleukin (IL)-1β and active caspase-1p10 release. The ATP-induced inflammasome activation and pyroptosis were markedly suppressed by an AMPK inhibitor compound C or small-interfering RNA-mediated knockdown of α, but could be greatly enhanced by metformin (a well-known AMPK agonist). Importantly, metformin administration increased the mortality of mice with bacterial sepsis, which was likely because metformin treatment enhanced the systemic inflammasome activation as indicated by elevated serum and hepatic IL-1β levels. Collectively, these data indicated that the AMPK signaling positively regulated ATP-induced inflammasome activation and pyroptosis in macrophages, highlighting the possibility of AMPK-targeting therapies for inflammatory diseases involving inflammasome activation.
在细菌感染以及无菌性组织损伤过程中，细菌和宿主细胞会释放三磷酸腺苷（ATP），其作为炎性小体激活的诱导剂。先前的研究表明，ATP处理会导致腺苷酸活化蛋白激酶（AMPK）激活。然而，尚不清楚AMPK信号是否参与了ATP诱导的炎性小体激活及随后的细胞焦亡的调控。在本研究中，我们旨在在脂多糖激活的小鼠巨噬细胞中探究这一问题。我们的结果显示，ATP处理后小鼠巨噬细胞中的AMPK信号被激活，同时伴有炎性小体激活和细胞焦亡，表现为细胞膜迅速破裂以及成熟白细胞介素（IL）-1β和活性半胱天冬酶-1 p10的释放。AMPK抑制剂化合物C或小干扰RNA介导的α敲低可显著抑制ATP诱导的炎性小体激活和细胞焦亡，但二甲双胍（一种著名的AMPK激动剂）可大大增强这种作用。重要的是，给予二甲双胍会增加细菌性败血症小鼠的死亡率，这可能是因为二甲双胍治疗增强了全身炎性小体激活，血清和肝脏IL-1β水平升高表明了这一点。总体而言，这些数据表明AMPK信号正向调控巨噬细胞中ATP诱导的炎性小体激活和细胞焦亡，突出了针对涉及炎性小体激活的炎症性疾病进行AMPK靶向治疗的可能性。
