Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Front Immunol. 2018 Jul 27;9:1742. doi: 10.3389/fimmu.2018.01742. eCollection 2018.
Migration of human plasmablast to the bone marrow is essential for the final differentiation of plasma cells and maintenance of effective humoral immunity. This migration is controlled by CXCL12/CXCR4-mediated activation of the protein kinase AKT. Herein, we show that the CXCL12-induced migration of human plasmablasts is dependent on glucose oxidation. Glucose depletion markedly inhibited plasmablast migration by 67%, and the glucose analog 2-deoxyglucose (2-DG) reduced the migration by 53%; conversely, glutamine depletion did not reduce the migration. CXCL12 boosted the oxygen consumption rate (OCR), and 2-DG treatment significantly reduced the levels of all measured tricarboxylic acid (TCA) cycle intermediates. AKT inhibitors blocked the CXCL12-mediated increase of OCR. CXCL12 enhanced the pyruvate dehydrogenase (PDH) activity by 13.5-fold in an AKT-dependent manner to promote mitochondrial oxidative phosphorylation. The knockdown and inhibition of PDH confirmed its indispensable role in CXCL12-induced migration. Cellular ATP levels fell by 91% upon exposure to 2-DG, and the mitochondrial ATP synthase inhibitor oligomycin inhibited CXCL12-induced migration by 85%. Low ATP levels inhibited the CXCL12-induced activation of AKT and phosphorylation of myosin light chains by 42%, which are required for cell migration. Thus, we have identified a mechanism that controls glucose oxidation AKT signaling and PDH activation, which supports the migration of plasmablasts. This mechanism can provide insights into the proper development of long-lived plasma cells and is, therefore, essential for optimal humoral immunity. To our knowledge, this study is the first to investigate metabolic mechanisms underlying human plasmablast migration toward CXCL12.
人类浆母细胞向骨髓的迁移对于浆细胞的最终分化和有效的体液免疫的维持至关重要。这种迁移受 CXCL12/CXCR4 介导的蛋白激酶 AKT 的激活所控制。在此，我们表明，人浆母细胞的 CXCL12 诱导迁移依赖于葡萄糖氧化。葡萄糖耗尽显著抑制浆母细胞迁移 67%，葡萄糖类似物 2-脱氧葡萄糖（2-DG）使迁移减少 53%；相反，谷氨酰胺耗尽不会减少迁移。CXCL12 增加耗氧率（OCR），2-DG 处理显著降低所有测量的三羧酸（TCA）循环中间产物的水平。AKT 抑制剂阻断了 CXCL12 介导的 OCR 增加。CXCL12 以 AKT 依赖的方式将丙酮酸脱氢酶（PDH）活性提高 13.5 倍，以促进线粒体氧化磷酸化。PDH 的敲低和抑制证实了其在 CXCL12 诱导迁移中的不可或缺的作用。暴露于 2-DG 时，细胞内 ATP 水平下降 91%，线粒体 ATP 合酶抑制剂寡霉素抑制 CXCL12 诱导的迁移 85%。低 ATP 水平抑制了 AKT 的 CXCL12 诱导激活和肌球蛋白轻链的磷酸化，这是细胞迁移所必需的。因此，我们已经确定了一种控制葡萄糖氧化 AKT 信号和 PDH 激活的机制，该机制支持浆母细胞的迁移。该机制可以深入了解长寿命浆细胞的正常发育，因此对最佳体液免疫至关重要。据我们所知，这项研究首次研究了人类浆母细胞向 CXCL12 迁移的代谢机制。
