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Inactivation of mitochondrial pyruvate carrier promotes NLRP3 inflammasome activation and gout development via metabolic reprogramming |
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| Authors: | Lih-Chyang Chen Yu-Jen Chen Hsin-An Lin Wu-Chien Chien Kuen-Jou Tsai Chi-Hsiang Chung Jui-Yang Wang Chien-Chou Chen Nan-Shih Liao Chieh-Tien Shih Yi-Ying Lin Chi-Ning Huang David M. Ojcius Kuo-Yang Huang Hsin-Chung Lin |
| Affiliation: | 1. Department of Medicine, MacKay Medical College, New Taipei City, Taiwan;2. Department of Medicine, MacKay Medical College, New Taipei City, Taiwan Department of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan Department of Artificial Intelligence and Medical Application, MacKay Junior College of Medicine, Nursing and Management, Taipei, Taiwan Department of Medical Research, China Medical University Hospital, Taichung, Taiwan;3. Division of Infection, Department of Medicine, Tri-Service General Hospital SongShan Branch, National Defense Medical Center, Taipei City, Taiwan Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei City, Taiwan;4. School of Public Health, National Defense Medical Center, Taipei City, Taiwan Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan Graduate Institute of Life Sciences, National Defense Medical Center, Taipei City, Taiwan;5. Department of Laboratory Medicine, MacKay Memorial Hospital, Taipei, Taiwan Department of Nursing, MacKay Medical College, New Taipei City, Taiwan;6. School of Public Health, National Defense Medical Center, Taipei City, Taiwan Taiwanese Injury Prevention and Safety Promotion Association, Taipei City, Taiwan;7. Department of Family Medicine, Tri-Service General Hospital SongShan Branch, National Defense Medical Center, Taipei City, Taiwan;8. Division of Nephrology, Department of Medicine, Tri-Service General Hospital SongShan Branch, National Defense Medical Center, Taipei City, Taiwan;9. Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan;10. Department of Nursing, MacKay Medical College, New Taipei City, Taiwan;11. Department of Biomedical Sciences, University of the Pacific, Arthur Dugoni School of Dentistry, San Francisco, California, USA;12. Graduate Institute of Pathology and Parasitology, National Defense Medical Center, Taipei City, Taiwan |
| Abstract: | 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. |
| Keywords: | gout mitochondrial pyruvate carrier NLRP3 inflammasome pioglitazone |