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 Shirts 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 HEAVENLY SLEEP LIQUID 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.