An enhanced mitochondrial function through glutamine metabolism in plasmablast differentiation in systemic lupus erythematosus
An enhanced mitochondrial function through glutamine metabolism in plasmablast differentiation in systemic lupus erythematosus
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DOI：
10.1093/rheumatology/keab824
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发表时间：
2021-11-03
期刊：
影响因子：
5.5
通讯作者：
Tanaka, Yoshiya
中科院分区：
文献类型：
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作者：
Sumikawa, Maiko Hajime;Iwata, Shigeru;Tanaka, Yoshiya
目的探讨系统性红斑狼疮（SLE）患者B细胞代谢紊乱及其与病理的关系。方法采用流式细胞术检测SLE患者和健康对照者外周血B细胞代谢标志物的表达。在体外，外周B细胞从HC和SLE患者分离，以研究参与其分化的代谢调节机制。结果SLE患者B细胞中DiOc 6（线粒体膜超极化）的表达水平高于HC，且与CD 19（+）细胞中浆母细胞的百分比和疾病活动性评分SLEDAI相关。用Toll样受体9（TLR 9）配体CpG和IFN-α刺激CD 19（+）细胞可增强体外糖酵解、氧化磷酸化（OXPHOS）、DiOc 6表达和成浆细胞分化。在没有谷氨酰胺的情况下，糖酵解和OXPHOS都减少，成浆细胞分化受到抑制，而在没有葡萄糖的情况下没有变化。由于谷氨酰胺是蛋白质合成的重要营养素，我们进一步研究了抑制谷氨酰胺降解的谷氨酰胺酶抑制剂BPTES对代谢调节的影响。BPTES降低DiOc 6表达、OXPHOS、活性氧（ROS）产生、三磷酸腺苷（ATP）产生、成浆细胞分化，而不影响糖酵解。二甲双胍抑制CpG和IFN-α诱导的谷氨酰胺摄取、线粒体功能和抑制成浆细胞分化。结论SLE患者B细胞线粒体功能障碍与成浆细胞分化和疾病活动有关。谷氨酰胺代谢介导的线粒体功能增强对浆母细胞分化具有重要意义，这可能是SLE潜在的治疗靶点。
Objective To evaluate the dysfunction of B-cell metabolism and its involvement in SLE pathology. Methods We assessed the expression of metabolic markers of B cells in the peripheral blood of healthy controls (HCs) and SLE patients by using flow cytometry. In vitro, peripheral B cells were isolated from HCs and SLE patients to investigate the metabolic regulation mechanisms involved in their differentiation. Results The expression level of DiOc6 (mitochondrial membrane hyperpolarization) was higher in B cells from SLE patients than in HCs, and correlated to the percentage of plasmablasts in CD19(+) cells and with SLEDAI, a disease activity score. Stimulation of CD19(+) cells with the Toll-like receptor 9 (TLR9) ligand CpG and IFN-alpha enhanced glycolysis, oxidative phosphorylation (OXPHOS), DiOc6 expression, and plasmablast differentiation in vitro. In the absence of glutamine, both glycolysis and OXPHOS were reduced, and plasmablast differentiation was suppressed, whereas there was no change in the absence of glucose. As glutamine is an important nutrient for protein synthesis, we further investigated the effect of the glutaminase inhibitor BPTES, which inhibits glutamine degradation, on metabolic regulation. BPTES reduced DiOc6 expression, OXPHOS, reactive oxygen species (ROS) production, adenosine triphosphate (ATP) production, plasmablast differentiation without affecting glycolysis. Metformin inhibited CpG- and IFN-alpha-induced glutamine uptake, mitochondrial functions and suppressed plasmablast differentiation. Conclusions Mitochondrial dysfunction in B cells is associated with plasmablast differentiation and disease activity in SLE. Enhanced mitochondrial functions mediated by glutamine metabolism are important for plasmablast differentiation, which may be a potential therapeutic target for SLE.