Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, School of Basic Medicine, Henan University, Kaifeng, China.
Clinical Laboratory, Huaihe Hospital, Henan University, Kaifeng, China.
J Cell Mol Med. 2020 Aug;24(15):8849-8861. doi: 10.1111/jcmm.15523. Epub 2020 Jun 18.
Uric acid crystal is known to activate the NLRP3 inflammasome and to cause tissue damages, which can result in many diseases, such as gout, chronic renal injury and myocardial damage. Meanwhile, soluble uric acid (sUA), before forming crystals, is also related to these diseases. This study was carried out to investigate whether sUA could also activate NLRP3 inflammasome in cardiomyocytes and to analyse the mechanisms. The cardiomyocyte activity was monitored, along with the levels of mature IL-1β and caspase-1 from H9c2 cells following sUA stimulus. We found that sUA was able to activate NLRP3 inflammasome, which was responsible for H9c2 cell apoptosis induced by sUA. By elevating TLR6 levels and then activating NF-κB/p65 signal pathway, sUA promoted NLRP3, pro-caspase 1 and pro-IL-1β production and provided the first signal of NLRP3 inflammasome activation. Meanwhile, ROS production regulated by UCP2 levels also contributed to NLRP3 inflammasome assembly and subsequent caspase 1 activation and mature IL-1β secretion. In addition, the tlr6 knockdown rats suffering from hyperuricemia showed the lower level of IL-1β and an ameliorative cardiac function. These findings suggest that sUA activates NLRP3 inflammasome in cardiomyocytes and they may provide one therapeutic strategy for myocardial damage induced by sUA.
尿酸晶体被认为可以激活 NLRP3 炎性体并导致组织损伤，从而导致许多疾病，如痛风、慢性肾损伤和心肌损伤。同时，可溶性尿酸（sUA）在形成晶体之前也与这些疾病有关。本研究旨在探讨 sUA 是否也可以在心肌细胞中激活 NLRP3 炎性体，并分析其机制。监测 H9c2 细胞在 sUA 刺激下的成熟 IL-1β 和 caspase-1 水平以及心肌细胞活性。我们发现 sUA 能够激活 NLRP3 炎性体，这是 sUA 诱导 H9c2 细胞凋亡的原因。通过提高 TLR6 水平，然后激活 NF-κB/p65 信号通路，sUA 促进 NLRP3、前胱天蛋白酶 1 和前 IL-1β 的产生，并提供 NLRP3 炎性体激活的第一信号。同时，UCP2 水平调节的 ROS 产生也有助于 NLRP3 炎性体的组装以及随后的 caspase 1 激活和成熟 IL-1β 的分泌。此外，患有高尿酸血症的 tlr6 敲低大鼠表现出较低水平的 IL-1β 和改善的心脏功能。这些发现表明 sUA 在心肌细胞中激活 NLRP3 炎性体，它们可能为 sUA 诱导的心肌损伤提供一种治疗策略。
