Inactivation of mitochondrial pyruvate carrier promotes NLRP3 inflammasome activation and gout development via metabolic reprogramming

The nucleotide‐binding and oligomerization domain, leucine‐rich repeats, and pyrin domain‐containing protein 3 (NLRP3) inflammasome plays a crucial role in innate immunity and is involved in the pathogenesis of autoinflammatory diseases. Glycolysis regulates NLRP3 inflammasome activation in macrophages. However, how lactic acid fermentation and pyruvate oxidation controlled by the mitochondrial pyruvate carrier (MPC) affect NLRP3 inflammasome activation and autoinflammatory disease remains elusive. We found that the inactivation of MPC with genetic depletion or pharmacological inhibitors, MSDC‐0160 or pioglitazone, increased NLRP3 inflammasome activation and IL‐1β secretion in macrophages. Glycolytic reprogramming induced by MPC inhibition skewed mitochondrial ATP‐associated oxygen consumption into cytosolic lactate production, which enhanced NLRP3 inflammasome activation in response to monosodium urate (MSU) crystals. As pioglitazone is an insulin sens MSDC‐itizer used for diabetes, its MPC inhibitory effect in diabetic individuals was investigated. The results showed that MPC inhibition exacerbated MSU‐induced peritonitis in diabetic mice and increased the risk of gout in patients with diabetes. Altogether, we found that glycolysis controlled by MPC regulated NLRP3 inflammasome activation and gout development. Accordingly, prescriptions for medications targeting MPC should consider the increased risk of NLRP3‐related autoinflammatory diseases. Inactivation of mitochondrial pyruvate carrier (MPC) with genetic depletion or pharmacological inhibitors pioglitazone or MSDC‐0160 blocks mitochondrial pyruvate import, thus reducing oxidative phosphorylation (OXPHOS) in macrophages. To compensate for energy demand, an increase in lactic fermentation maintains glycolysis through the NAD+ cycle to make glycolytic ATP but is also accompanied by lactate production. When combined with insulin therapy, insulin enables cells to take up glucose to promote lactate fermentation, maximizing lactate production. Cellular lactate controlled by MPC contributes to upgrading NOD, LRR, and pyrin domain‐containing protein 3 (NLRP3) inflammasome hyperactivation and exacerbating gout development. Downregulation of lactate production by the lactate dehydrogenase (LDH) inhibitor GSK2837808A efficiently prevented NLRP3 inflammasome activation.