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

IF 4.9 3区 医学 Q2 IMMUNOLOGY Immunology Pub Date : 2024-06-27 DOI:10.1111/imm.13827
Kun-Long Duan, Tian-Xiang Wang, Jian-Wei You, Hai-Ning Wang, Zhi-Qiang Wang, Zi-Xuan Huang, Jin-Ye Zhang, Yi-Ping Sun, Yue Xiong, Kun-Liang Guan, Dan Ye, Li Chen, Ronghua Liu, Hai-Xin Yuan
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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.

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PCK2 保护抗体分泌细胞免受氧化应激,从而维持肠道平衡并预防结肠炎。
维持细胞内氧化还原平衡对免疫球蛋白 A(IgA)抗体分泌细胞(ASCs)的存活、抗体分泌和粘膜免疫平衡至关重要。然而,线粒体代谢酶与 ASCs 中氧化还原平衡之间的关系还有待全面研究。我们的研究揭示了线粒体酶 PCK2 在调节 ASCs 氧化还原平衡和肠道稳态中的关键作用。我们发现,PCK2 的缺失(无论是整体缺失还是 B 细胞缺失)会加剧右旋糖酐硫酸钠(DSS)诱导的结肠炎,原因是 IgA ASC 细胞死亡增加和抗体产生减少。从机理上讲,PCK2 的缺失会使谷氨酰胺进入 TCA 循环,导致 TCA 通量增加和线粒体活性氧(mtROS)产生过多。此外,PCK2 的缺失还减少了谷胱甘肽(GSH)合成所需的谷氨酰胺,导致总谷胱甘肽水平下降。mtROS的升高和GSH的降低使ASCs面临巨大的氧化应激,最终导致细胞凋亡。重要的是,我们发现线粒体靶向抗氧化剂线醌(Mito-Q)可以减轻 PCK2 缺乏对 IgA ASCs 的不利影响,从而缓解小鼠结肠炎。我们的研究结果凸显了 PCK2 在 IgA ASC 存活过程中的关键作用,并为结肠炎治疗提供了一个潜在的新靶点。
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来源期刊
Immunology
Immunology 医学-免疫学
CiteScore
11.90
自引率
1.60%
发文量
175
审稿时长
4-8 weeks
期刊介绍: Immunology is one of the longest-established immunology journals and is recognised as one of the leading journals in its field. We have global representation in authors, editors and reviewers. Immunology publishes papers describing original findings in all areas of cellular and molecular immunology. High-quality original articles describing mechanistic insights into fundamental aspects of the immune system are welcome. Topics of interest to the journal include: immune cell development, cancer immunology, systems immunology/omics and informatics, inflammation, immunometabolism, immunology of infection, microbiota and immunity, mucosal immunology, and neuroimmunology. The journal also publishes commissioned review articles on subjects of topical interest to immunologists, and commissions in-depth review series: themed sets of review articles which take a 360° view of select topics at the heart of immunological research.
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