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Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation

Author

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  • Yafeng Li

    (University of Texas Southwestern Medical Center)

  • Jessica S. Hook

    (University of Texas Southwestern Medical Center)

  • Qing Ding

    (University of Texas Southwestern Medical Center)

  • Xue Xiao

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Stephen S. Chung

    (University of Texas Southwestern Medical Center)

  • Marcel Mettlen

    (University of Texas Southwestern Medical Center)

  • Lin Xu

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Jessica G. Moreland

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Michalis Agathocleous

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

Abstract

Severe COVID-19 is characterized by an increase in the number and changes in the function of innate immune cells including neutrophils. However, it is not known how the metabolome of immune cells changes in patients with COVID-19. To address these questions, we analyzed the metabolome of neutrophils from patients with severe or mild COVID-19 and healthy controls. We identified widespread dysregulation of neutrophil metabolism with disease progression including in amino acid, redox, and central carbon metabolism. Metabolic changes in neutrophils from patients with severe COVID-19 were consistent with reduced activity of the glycolytic enzyme GAPDH. Inhibition of GAPDH blocked glycolysis and promoted pentose phosphate pathway activity but blunted the neutrophil respiratory burst. Inhibition of GAPDH was sufficient to cause neutrophil extracellular trap (NET) formation which required neutrophil elastase activity. GAPDH inhibition increased neutrophil pH, and blocking this increase prevented cell death and NET formation. These findings indicate that neutrophils in severe COVID-19 have an aberrant metabolism which can contribute to their dysfunction. Our work also shows that NET formation, a pathogenic feature of many inflammatory diseases, is actively suppressed in neutrophils by a cell-intrinsic mechanism controlled by GAPDH.

Suggested Citation

  • Yafeng Li & Jessica S. Hook & Qing Ding & Xue Xiao & Stephen S. Chung & Marcel Mettlen & Lin Xu & Jessica G. Moreland & Michalis Agathocleous, 2023. "Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37567-w
    DOI: 10.1038/s41467-023-37567-w
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