2. Academic Validation
  3. PCK2 maintains intestinal homeostasis and prevents colitis by protecting antibody-secreting cells from oxidative stress

PCK2 maintains intestinal homeostasis and prevents colitis by protecting antibody-secreting cells from oxidative stress

  • Immunology. 2024 Jun 27. doi: 10.1111/imm.13827.
Kun-Long Duan 1,  Tian-Xiang Wang 1,  Jian-Wei You 2,  Hai-Ning Wang 1,  Zhi-Qiang Wang 3,  Zi-Xuan Huang 1,  Jin-Ye Zhang 1,  Yi-Ping Sun 1,  Yue Xiong 4,  Kun-Liang Guan 5,  Dan Ye 6,  Li Chen 2,  Ronghua Liu 7,  Hai-Xin Yuan 1 8
Affiliations

Affiliations

  • 1 Shanghai Fifth People's Hospital, Molecular and Cell Biology Research Lab of Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 2 Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
  • 3 Department of Immunology, School of Basic Medical Sciences, Shanghai Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 4 Cullgen Inc., San Diego, California, USA.
  • 5 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California, USA.
  • 6 Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital of Fudan University, Key Laboratory of Metabolism and Molecular Medicine (Ministry of Education), Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Molecular and Cell Biology Research Lab of Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
  • 7 Shanghai Fifth People's Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 8 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing Medical University, Chongqing, China.
PMID: 38934051 DOI: 10.1111/imm.13827
Abstract

Maintaining intracellular redox balance is essential for the survival, antibody secretion, and mucosal immune homeostasis of immunoglobulin A (IgA) antibody-secreting cells (ASCs). However, the relationship between mitochondrial metabolic Enzymes and the redox balance in ASCs has yet to be comprehensively studied. Our study unveils the pivotal role of mitochondrial Enzyme PCK2 in regulating ASCs' redox balance and intestinal homeostasis. We discover that PCK2 loss, whether globally or in B cells, exacerbates dextran sodium sulphate (DSS)-induced colitis due to increased IgA ASC cell death and diminished antibody production. Mechanistically, the absence of PCK2 diverts glutamine into the TCA cycle, leading to heightened TCA flux and excessive mitochondrial Reactive Oxygen Species (mtROS) production. In addition, PCK2 loss reduces glutamine availability for glutathione (GSH) synthesis, resulting in a decrease of total glutathione level. The elevated mtROS and reduced GSH expose ASCs to overwhelming oxidative stress, culminating in cell Apoptosis. Crucially, we found that the mitochondria-targeted antioxidant Mitoquinone (Mito-Q) can mitigate the detrimental effects of PCK2 deficiency in IgA ASCs, thereby alleviating colitis in mice. Our findings highlight PCK2 as a key player in IgA ASC survival and provide a potential new target for colitis treatment.

Keywords

B cell; mucosal immunology; reactive oxygen species.

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