mTORC1-Induced HK1-Dependent Glycolysis Regulates NLRP3 Inflammasome Activation

• Inhibition of mTORC1 suppresses NLRP3 inflammasome activation
• Raptor/mTORC1 regulates HK1-dependent glycolysis
• HK1-dependent glycolysis is critical for NLRP3 inflammasome activation
• Activation of the glycolytic phenotype is linked to NLRP3 inflammasome activation

SummaryThe mammalian target of rapamycin complex 1 (mTORC1) regulates activation of immune cells and cellular energy metabolism. Although 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-1β 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.

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