Luo Yunhai, Zheng Daofeng, Mou Tong, Pu Junliang, Huang Zuotian, Chen Wei, Zhang Yuke, Wu Zhongjun
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Exp Ther Med. 2021 Dec;22(6):1358. doi: 10.3892/etm.2021.10793. Epub 2021 Sep 24.
Cytidine monophosphate kinase 2 (CMPK2) is a mitochondrial nucleotide monophosphate kinase which is important for the substrates of mitochondrial DNA synthesis and has been reported to participate in macrophage activation and the inflammatory response. The purpose of the present research was to determine the potential role of CMPK2 in hepatic ischemia/reperfusion (I/R) injury and to elucidate the underlying molecular mechanisms. The present study investigated the role of CMPK2 in regulating the NLRP3 pathway and liver dysfunction induced by hepatic I/R both and . It was revealed that hypoxia/reoxygenation (H/R) treatment enhanced the mRNA expression levels of CMPK2, NLRP3, IL-18, IL-1β and TNF-α in RAW 264.7 cells. The protein expression levels of IL-18, IL-1β and cleaved-caspase-1 were decreased following CMPK2 knockdown. Furthermore, the inhibition of AIM2 downregulated the expression level of IL-1β, IL-18 and cleaved-caspase-1 in the CMPK2 knockdown group followed by H/R treatment, while the inhibition of NLRP3 did not. CMPK2 deficiency also decreased alanine aminotransferase and aspartate aminotransferase expression in mice serum, as well as the pathological changes in the liver. Similarly, the release of IL-18 and IL-1β in mouse serum was also restrained with the decline of CMPK2. In conclusion, the results of the present study demonstrate that CMPK2 is indispensable for NLRP3 inflammasome activation, making CMPK2 an effective target to relieve the liver from I/R injury. In addition, the function of CMPK2 is closely associated with NLRP3 inflammasome activation, instead of AIM2.
胞苷单磷酸激酶2（CMPK2）是一种线粒体核苷酸单磷酸激酶，对线粒体DNA合成的底物很重要，据报道它参与巨噬细胞活化和炎症反应。本研究的目的是确定CMPK2在肝缺血/再灌注（I/R）损伤中的潜在作用，并阐明其潜在的分子机制。本研究调查了CMPK2在调节NLRP3通路和肝I/R诱导的肝功能障碍中的作用。结果显示，缺氧/复氧（H/R）处理增强了RAW 264.7细胞中CMPK2、NLRP3、IL-18、IL-1β和TNF-α的mRNA表达水平。CMPK2基因敲低后，IL-18、IL-1β和裂解的半胱天冬酶-1的蛋白表达水平降低。此外，在CMPK2基因敲低组随后进行H/R处理时，抑制AIM2可下调IL-1β、IL-18和裂解的半胱天冬酶-1的表达水平，而抑制NLRP3则没有这种作用。CMPK2缺乏还降低了小鼠血清中丙氨酸氨基转移酶和天冬氨酸氨基转移酶的表达，以及肝脏的病理变化。同样，随着CMPK2的下降，小鼠血清中IL-18和IL-1β的释放也受到抑制。总之，本研究结果表明CMPK2对NLRP3炎性小体激活不可或缺，使CMPK2成为缓解肝脏I/R损伤的有效靶点。此外，CMPK2的功能与NLRP3炎性小体激活密切相关，而不是与AIM2相关。
