RETRACTED: mTORC1-Induced HK1-Dependent Glycolysis Regulates NLRP3 Inflammasome Activation

Abstract

SUMMARY The mammalian target of rapamycin complex 1 (mTORC1) regulates activation of immune cells and cellular energy metabolism. While glycolysis has been linked to immune functions, the mechanisms by which glycolysis regulates NLRP3 inflammasome activation remain unclear. Here, we demonstrate that mTORC1-induced glycolysis provides an essential mechanism for NLRP3 inflammasome activation. Moreover, we demonstrate that hexokinase 1 (HK1)-dependent glycolysis, under the regulation of mTORC1, represents a critical metabolic pathway for NLRP3 inflammasome activation. Downregulation of glycolysis by inhibition of Raptor/mTORC1 or HK1 suppressed both pro-IL-1 β maturation and caspase-1 activation in macrophages in response to LPS and ATP. These results suggest that upregulation of HK1-dependent glycolysis by mTORC1 regulates NLRP3 inflammasome activation.

Cytoprotective activated protein C averts Nlrp3 inflammasome–induced ischemia-reperfusion injury via mTORC1 inhibition

“…To this end, we determined expression of Raptor (regulatoryassociated protein of mTOR) and HK1 as well as total and phosphorylated ribosomal p70-S6 kinase (p70S6K) in BMDMs, neonatal cardiac fibroblasts, and neonatal cardiomyocytes. Expression of Raptor and HK1 and phosphorylation of p70S6K were enhanced in LPSprimed ATP-stimulated BMDMs and neonatal cardiac fibroblasts (Figure 4A-B; supplemental Figure 2A-B), 40 as well as in neonatal cardiomyocytes subjected to H/R ( Figure 4C; supplemental Figure 2C). Treatment with aPC normalized expression of Raptor and HK1 and p70S6K phosphorylation levels in LPS-primed and ATP-stimulated cells or in H/R-injured primary cardiomyocytes (Figure 4A-C; supplemental Figure 2A-C).…”

“…After 1 hour, cells were exposed to adenosine triphosphate (ATP) or PBS (control) for 3 hours to activate the Nlrp3 inflammasome. 39,40 The LPS/ATPmediated induction of Nlrp3 expression and cl-Casp1 and cl-IL-1b were prevented by aPC in all 3 cell types ( Figure 3A-F). Thus, aPC dampens inflammasome activation not only in innate immune cells but also in resident cardiac cells.…”

“…21 Furthermore, mTOR complex 1 (mTORC1), which is negatively regulated by AMPK, was recently shown to activate Nlrp3 inflammasome in macrophages via hexokinase 1 (HK1). 40 Hence, we speculated that aPC restricts inflammasome activation by restricting mTORC1 signaling in the setting of myocardial IRI. To this end, we determined expression of Raptor (regulatoryassociated protein of mTOR) and HK1 as well as total and phosphorylated ribosomal p70-S6 kinase (p70S6K) in BMDMs, neonatal cardiac fibroblasts, and neonatal cardiomyocytes.…”

Inflammasome Priming in Sterile Inflammatory Disease

“…One study demonstrated that 2DG only inhibited IL-1 production when added before the LPS priming step, suggesting that it might limit pro-IL-1 and NLRPγ priming [35] . By comparison, other work showed that addition of 2DG after LPS, and before ATP, could affect NLRP3 inflammasome activation (signal 2) to generate mature IL-1 [32] . Unexpectedly, in the latter study 2DG treatment had no effect on NLRP3 levels.…”

“…For example, 2-deoxyglucose (2DG) -a potent inhibitor of glycolysis -has been shown to suppress LPS-induced pro-IL-1 expression [31,32,33] and more recently has been found to limit ROS production in response to LPS and ATP, suggesting that its inhibitory effects may be at least partially ROS-dependent [32] . 2DG also inhibits NF-κB, and is thereby likely to impair NLRP3 expression and priming [34].…”