mTOR Modulates NLRP3 Inflammasome Activation via Nuclear Translocation and STAT1 Inhibition

The NLRP3 inflammasome has emerged as an unexpected sensor of metabolic danger and stress. Their enhanced activation has been implicated in the development of major diseases such as gout, Type 2 diabetes, obesity, cancer, and neurodegenerative and cardiovascular diseases. In this study, we showed that mammalian target of rapamycin (mTOR) regulates NLRP3 inflammasome activation in the nucleus of macrophages. mTOR binds to NLRP3 under basal conditions, and this binding is reduced after lipopolysaccharides (LPS) or LPS + adenosine triphosphate (ATP) treatment. Furthermore, rapamycin-induced downregulation of mTOR expression has an inhibitory effect on NLRP3 inflammasome activation. mTOR knockdown (KD) mice exhibit reduced protein levels of inflammasome components, and their macrophages fail to activate the NLRP3 inflammasome after LPS + ATP treatment. From a mechanistic point of view, LPS + ATP treatment induced the nuclear translocation of mTOR, leading to enhanced NLRP3 inflammasome activation. However, the mTOR inhibition by rapamycin treatment increased phosphorylation of STAT1 which repressed NLRP3 activation. When rapamycin was combined with the STAT1 inhibitor fludarabine, NLRP3 inflammasome activity was restored. Taken together, these findings suggest a role for mTOR in NLRP3 regulation and identify a potential therapeutic option for controlling inflammasome activation.