2. Academic Validation
  3. Inactivation of mitochondrial pyruvate carrier promotes NLRP3 inflammasome activation and gout development via metabolic reprogramming

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

  • Immunology. 2023 Jan 28. doi: 10.1111/imm.13628.
Lih-Chyang Chen 1,  Yu-Jen Chen 1 2 3 4 5,  Hsin-An Lin 6 7,  Wu-Chien Chien 8 9 10,  Kuen-Jou Tsai 11 12,  Chi-Hsiang Chung 8 13,  Jui-Yang Wang 14,  Chien-Chou Chen 15,  Nan-Shih Liao 16,  Chieh-Tien Shih 1,  Yi-Ying Lin 12,  Chi-Ning Huang 1,  David M Ojcius 17,  Kuo-Yang Huang 18,  Hsin-Chung Lin 18 19
Affiliations

Affiliations

  • 1 Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.
  • 2 Department of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan.
  • 3 Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan.
  • 4 Department of Artificial Intelligence and Medical Application, MacKay Junior College of Medicine, Nursing and Management, Taipei, Taiwan.
  • 5 Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
  • 6 Division of Infection, Department of Medicine, Tri-Service General Hospital SongShan Branch, National Defense Medical Center, Taipei City, Taiwan.
  • 7 Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei City, Taiwan.
  • 8 School of Public Health, National Defense Medical Center, Taipei City, Taiwan.
  • 9 Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan.
  • 10 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei City, Taiwan.
  • 11 Department of Laboratory Medicine, MacKay Memorial Hospital, Taipei, Taiwan.
  • 12 Department of Nursing, MacKay Medical College, New Taipei City, Taiwan.
  • 13 Taiwanese Injury Prevention and Safety Promotion Association, Taipei City, Taiwan.
  • 14 Department of Family Medicine, Tri-Service General Hospital SongShan Branch, National Defense Medical Center, Taipei City, Taiwan.
  • 15 Division of Nephrology, Department of Medicine, Tri-Service General Hospital SongShan Branch, National Defense Medical Center, Taipei City, Taiwan.
  • 16 Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
  • 17 Department of Biomedical Sciences, University of the Pacific, Arthur Dugoni School of Dentistry, San Francisco, CA, USA.
  • 18 Graduate Institute of Pathology and Parasitology, National Defense Medical Center, Taipei City, Taiwan.
  • 19 Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan.
PMID: 36708143 DOI: 10.1111/imm.13628
Abstract

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.

Keywords

Gout; Mitochondrial pyruvate carrier; NLRP3 inflammasome; Pioglitazone.

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