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Neutrophil glucose flux as a therapeutic target in antiphospholipid syndrome
Ajay Tambralli, … , Costas A. Lyssiotis, Jason S. Knight
Ajay Tambralli, … , Costas A. Lyssiotis, Jason S. Knight
Published June 13, 2024
Citation Information: J Clin Invest. 2024;134(15):e169893. https://doi.org/10.1172/JCI169893.
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Research Article Autoimmunity Article has an altmetric score of 54

Neutrophil glucose flux as a therapeutic target in antiphospholipid syndrome

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Abstract

Neutrophil hyperactivity and neutrophil extracellular trap release (NETosis) appear to play important roles in the pathogenesis of the thromboinflammatory autoimmune disease known as antiphospholipid syndrome (APS). The understanding of neutrophil metabolism has advanced tremendously in the past decade, and accumulating evidence suggests that a variety of metabolic pathways guide neutrophil activities in health and disease. Our previous work characterizing the transcriptome of APS neutrophils revealed that genes related to glycolysis, glycogenolysis, and the pentose phosphate pathway (PPP) were significantly upregulated. Here, we found that neutrophils from patients with APS used glycolysis more avidly than neutrophils from people in the healthy control group, especially when the neutrophils were from patients with APS with a history of microvascular disease. In vitro, inhibiting either glycolysis or the PPP tempered phorbol myristate acetate– and APS IgG–induced NETosis, but not NETosis triggered by a calcium ionophore. In mice, inhibiting either glycolysis or the PPP reduced neutrophil reactive oxygen species production and suppressed APS IgG–induced NETosis ex vivo. When APS-associated thrombosis was evaluated in mice, inhibiting either glycolysis or the PPP markedly suppressed thrombosis and circulating NET remnants. In summary, these data identify a potential role for restraining neutrophil glucose flux in the treatment of APS.

Authors

Ajay Tambralli, Alyssa Harbaugh, Somanathapura K. NaveenKumar, Megan D. Radyk, Christine E. Rysenga, Kaitlyn Sabb, Julia M. Hurley, Gautam J. Sule, Srilakshmi Yalavarthi, Shanea K. Estes, Claire K. Hoy, Tristin Smith, Cyrus Sarosh, Jacqueline A. Madison, Jordan K. Schaefer, Suman L. Sood, Yu Zuo, Amr H. Sawalha, Costas A. Lyssiotis, Jason S. Knight

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Figure 6

In mouse neutrophils, APS IgG promotes NETosis, 2-NBDG uptake, and glycolysis that can be restrained by 2-DG.

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In mouse neutrophils, APS IgG promotes NETosis, 2-NBDG uptake, and glyco...
(A) Timeline of treatment with saline or 2-DG (0.5 g/kg), intraperitoneal IgG administration, and peritoneal neutrophil isolation. Each point represents 1 mouse; n = 5 for control IgG + saline, n = 8 for APS IgG + saline, and n = 5 for APS IgG + 2-DG. (B) 2-NBDG fluorescence was measured using flow cytometry. (C) Glycolytic capacity was measured using the glycolysis stress test. (D) Spontaneous NETosis was characterized using SYTOX Green. For C and D, data are presented as fold change in the APS IgG-treated mice compared with the control IgG-treated mice. (E) Total cellular ROS production was measured with DCFDA fluorescence. For all, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 using 1-way ANOVA with Holm-Šidák’s multiple comparison test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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