Pharmacologically Inferred Glycolysis and Glutaminolysis Requirement of B Cells in Lupus-Prone Mice.
Pharmacologically Inferred Glycolysis and Glutaminolysis Requirement of B Cells in Lupus-Prone Mice.
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DOI：
10.4049/jimmunol.2100356
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发表时间：
2022-05-01
影响因子：
4.4
通讯作者：
Morel, Laurence
中科院分区：
文献类型：
--
作者：
Choi, Seung-Chul;Li, Wei;Zhang, Xiaojuan;Kanda, Nathalie;Zeumer-Spataro, Leilani;Teng, Xiangyu;Morel, Laurence
几项研究表明，狼疮患者和狼疮易感小鼠的CD 4 + T细胞代谢增强。对狼疮B细胞的代谢知之甚少。在这里，我们比较了在稳态下，以及在T细胞依赖性（TD）和T细胞非依赖性（TI）免疫期间，狼疮倾向B6.Sle1.Sle2.Sle3（TC）小鼠和B6对照小鼠之间B细胞的代谢。在自身免疫发病之前开始，TC小鼠的B细胞显示出糖酵解和线粒体呼吸升高，其通过用2-脱氧-D-葡萄糖（2DG）处理抑制糖酵解而在体内正常化。2DG大大降低了TI抗原特异性抗体的产生，但对TD抗原的影响最小。相反，在两种菌株中，用6-重氮-5-氧代-L-正亮氨酸（DON）抑制去甲氨醇分解对TD的影响大于TI Ag特异性抗体。然而，对体外纯化的B细胞中TI和TD反应的分析表明，谷氨酰胺分解要求不是B细胞固有的。因此，B细胞对TI中糖酵解的需求比TD-反应更大，如从药理学干预推断的。来自狼疮易感小鼠和对照小鼠的B细胞具有不同的内在代谢需求，或对2DG和DON的不同反应。这反映了我们以前用滤泡辅助T细胞获得的结果。总体而言，这些结果预测，靶向葡萄糖代谢可能通过消除自身反应性TFH和B细胞为全身性自身免疫提供有效的治疗方法，尽管它也可能损害TI反应。
Several studies have shown an enhanced metabolism in the CD4+ T cells of lupus patients and lupus-prone mice. Little is known on the metabolism of B cells in lupus. Here we compared the metabolism of B cells between lupus-prone B6.Sle1.Sle2.Sle3 (TC) mice and B6 controls at steady state relative to autoantibody production, as well as during T cell-dependent (TD) and T cell-independent (TI) immunizations. Starting before the onset of autoimmunity, B cells from TC mice showed an elevated glycolysis and mitochondrial respiration, which were normalized in vivo by inhibiting glycolysis with a 2-deoxy-D-glucose (2DG) treatment. 2DG greatly reduced the production of TI-antigen-specific antibodies, but showed minimal effect with TD-antigens. In contrast, the inhibition of glutaminolysis with 6-Diazo-5-oxo-L-norleucine (DON) had a greater effect on TD than TI Ag-specific antibodies in both strains. Analysis of the TI and TD responses in purified B cells in vitro suggests, however, that the glutaminolysis requirement is not B cell-intrinsic. Thus, B cells have a greater requirement for glycolysis in TI than TD-responses, as inferred from pharmacological interventions. B cells from lupus-prone and control mice have different intrinsic metabolic requirement, or different responses towards 2DG and DON. which mirrors our previous results obtained with follicular helper T cells. Overall, these results predict that targeting glucose metabolism may provide an effective therapeutic approach for systemic autoimmunity by eliminating both autoreactive TFH and B cells, although it may also impair TI-responses.
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影响因子：
16.6
作者：
Choi SC;Titov AA;Abboud G;Seay HR;Brusko TM;Roopenian DC;Salek-Ardakani S;Morel L
通讯作者：
Morel L
影响因子：
7.3
作者：
Bacalao MA;Satterthwaite AB
通讯作者：
Satterthwaite AB
影响因子：
4.4
作者：
Dufort, Fay J.;Bleiman, Blair F.;Chiles, Thomas C.
通讯作者：
Chiles, Thomas C.
影响因子：
4.4
作者：
Jayachandran, Nipun;Mejia, Edgard M.;Marshall, Aaron J.
通讯作者：
Marshall, Aaron J.
影响因子：
4.4
作者：
Sang, Allison;Niu, Haitao;Morel, Laurence
通讯作者：
Morel, Laurence