In Immunology ; h5-index 53.0
The 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 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 sensitizer 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. This article is protected by copyright. All rights reserved.
Chen Lih-Chyang, Chen Yu-Jen, Lin Hsin-An, Chien Wu-Chien, Tsai Kuen-Jou, Chung Chi-Hsiang, Wang Jui-Yang, Chen Chien-Chou, Liao Nan-Shih, Shih Chieh-Tien, Lin Yi-Ying, Huang Chi-Ning, Ojcius David M, Huang Kuo-Yang, Lin Hsin-Chung
2023-Jan-28
Gout, Mitochondrial pyruvate carrier, NLRP3 inflammasome, Pioglitazone
