TIGAR deficiency induces caspase-1-dependent trophoblasts pyroptosis through NLRP3-ASC inflammasome

IntroductionGestational diabetes mellitus (GDM), a common complication of pregnancy, is risky for both mother and fetus. Previous studies about TP53-induced glycolysis and apoptosis regulator (TIGAR) focused on the occurrence and development of cancer, cardiovascular disease, and neurological disease, however, it is still unclear whether TIGAR plays a regulatory role in gestational diabetes mellitus (GDM). MethodsUtilizing HG exposure, we explored the role of TIGAR in oxidative stress limitation, excessive inflammatory toxicity defense, and pyroptosis prevention. ResultsTIGAR was up-regulated in vivo and in vitro under HG condition, and loss of TIGAR increased ROS in trophoblast cells which drove a phenotypic switch and hindered the capacity of migration, invasion, and tube formation. This switch depended on the increased activation of NLRP3-ASC-caspase-1 signaling, which caused a distinctive characteristic of pyroptosis, and these findings could finally be reverted by antioxidant treatment (NAC) and receptor block (MCC950). Collectively, trophoblast pyroptosis is an upstream event of TIGAR deficiency-induced inflammation, which is promoted by ROS accumulation through NLRP3-ASC inflammasome. ConclusionTaken together, our results uncovered that, as the upstream event of TIGAR deficiency-induced inflammation, pyroptosis is stimulated by ROS accumulation through NLRP3-ASC inflammasome.

Automated summary

Through the study, it was found that TIGAR is up-regulated under high glucose conditions in vivo and in vitro, and loss of TIGAR increases ROS levels in trophoblast cells, leading to phenotypic changes and inhibition of migration, invasion, and tube formation. This switch is caused by the activation of the NLRP3-ASC-caspase-1 signaling pathway, resulting in pyroptosis. These findings can be reversed by antioxidant treatment and receptor blockage. In conclusion, trophoblast pyroptosis is an upstream event of TIGAR deficiency-induced inflammation, which is promoted by ROS accumulation through NLRP3-ASC inflammasome.