College of Life Science, Northeast Agricultural University, Harbin, 150030, PR China.
College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, PR China.
Fish Shellfish Immunol. 2022 Dec;131:127-136. doi: 10.1016/j.fsi.2022.09.071. Epub 2022 Oct 3.
Lead (Pb) has been concerned as one of the most severe hazardous contaminants, because it can cause pyroptosis in multiple tissues of mammals and birds. Melatonin (Mel) has attracted much interest for its role in governing intestinal injury via microRNAs (miRNAs). To explore the effect of Mel on Pb exposure-induced intestinal epithelial cell pyroptosis in common carps by regulating miR-17-5p/TXNIP axis, the Pb exposure and Pb-Mel treated models were constructed in vivo. The results elucidated that the suppressed expression of miR-17-5p and intensified level of TXNIP were primarily detected in Pb-exposed gut tissues, and both abolished with Mel addition, along with downregulated Pb-mediated elevated expression of NLRP3, CASP1, IL1β and GSDMD. Additionally, the targeting relationship between miR-17-5p and TXNIP were demonstrated by dual-luciferase reporter assay, and on this basis, miR-17-5p NC, mimic and inhibitor cell models were established. Thereby, Thereby, the expression of TXNIP in the miR-17-5p mimic groups was significant lower in the Pb-exposure but still elevated than the Control group, and the expression of NLRP3 and NLRP3-dependent pyrotposis-related genes performed consistent alterations. Noticeably, the expression of TXNIP suppressed with Mel addition even in the miR-17-5p inhibitor cell model, resulting in the inactivation of NLRP3 inflammasome-dependent pyroptosis. Overall, we draw the conclusion as Mel attenuates Pb-induced intestinal epithelial cell pyroptosis via miR-17-5p/TXNIP axis. The present study provides a novel perspective for toxicological mechanism of Pb, and new insights for the detoxification mechanism of Mel.
铅（Pb）一直被认为是最严重的危险污染物之一，因为它可以导致哺乳动物和鸟类的多种组织发生细胞焦亡。褪黑素（Mel）因其在通过 microRNAs（miRNAs）调控肠道损伤方面的作用而受到广泛关注。为了探讨 Mel 通过调节 miR-17-5p/TXNIP 轴对鲤鱼肠道上皮细胞铅暴露诱导的细胞焦亡的影响，在体内构建了铅暴露和铅-Mel 处理模型。结果表明，在铅暴露的肠道组织中，miR-17-5p 的表达受到抑制，TXNIP 的水平增强，而添加 Mel 则可以消除这两种情况，并降低铅介导的 NLRP3、CASP1、IL1β 和 GSDMD 的上调表达。此外，通过双荧光素酶报告基因实验证明了 miR-17-5p 和 TXNIP 之间的靶向关系，并在此基础上建立了 miR-17-5p NC、mimic 和 inhibitor 细胞模型。因此，在铅暴露的情况下，miR-17-5p mimic 组的 TXNIP 表达显著降低，但仍高于对照组，而 NLRP3 和 NLRP3 依赖性细胞焦亡相关基因的表达也发生了一致的改变。值得注意的是，即使在 miR-17-5p inhibitor 细胞模型中添加 Mel 也可以抑制 TXNIP 的表达，从而使 NLRP3 炎性小体依赖性细胞焦亡失活。总之，我们得出结论，Mel 通过 miR-17-5p/TXNIP 轴减轻铅诱导的肠道上皮细胞细胞焦亡。本研究为铅的毒理学机制提供了新的视角，为 Mel 的解毒机制提供了新的见解。
