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Front Immunol. 2018 Jul 27;9:1742. doi: 10.3389/fimmu.2018.01742. eCollection 2018.

Human Plasmablast Migration Toward CXCL12 Requires Glucose Oxidation by Enhanced Pyruvate Dehydrogenase Activity via AKT.

Pak HK1,2, Nam B1,2, Lee YK1,2, Kim YW1,2, Roh J3, Son J4, Chung YS5, Choe J6, Park CS1,2.

Author information

1
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
2
Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
3
Department of Pathology, Ajou University School of Medicine, Suwon, South Korea.
4
Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, South Korea.
5
Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
6
Department of Microbiology and Immunology, School of Medicine, Kangwon National University, Chuncheon, South Korea.

Abstract

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 via 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.

KEYWORDS:

AKT; ATP; CXCL12; glucose oxidation; humoral immunity; myosin light chain; plasmablast; pyruvate dehydrogenase

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