Fig. 2

Immunometabolic regulation of NLRP3 inflammasome activity. The glycolytic cascade downstream of active PKM2 drives the production of lactate, which mediates EIF2AK2 phosphorylation and enhances IL-β-mediated PFKFB3 expression to activate NLRP3. Dimeric PKM2 interacts with HIF-1α, thus promoting IL-β expression and glycolysis. Bacterial NAG binds to and inhibits HK activity, which causes the dissociation of HK from VDACs and in turn releases unknown factors from mitochondria to trigger NLRP3 inflammasome activation. Aberrant mitochondrial homeostasis results in the accumulation of the TCA derivatives succinate (in green) and itaconate (in blue), which activate and suppress NLRP3, respectively. Reduced NAD⁺ availability inactivates SIRT1/2, resulting in two activation signals for NLRP3: (i) AMPK inhibition and (ii) the deposition of acetylated α-tubulin. Green: inducers of NLRP3 activity. Blue: inhibitors of NLRP3