Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation
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 ne...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-37567-w |
| _version_ | 1797832052346716160 |
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| author | Yafeng Li Jessica S. Hook Qing Ding Xue Xiao Stephen S. Chung Marcel Mettlen Lin Xu Jessica G. Moreland Michalis Agathocleous |
| author_facet | Yafeng Li Jessica S. Hook Qing Ding Xue Xiao Stephen S. Chung Marcel Mettlen Lin Xu Jessica G. Moreland Michalis Agathocleous |
| author_sort | Yafeng Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T14:01:35Z |
| format | Article |
| id | doaj.art-d8af6e23b4bc43b68061b3cd5ae0f3dd |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T14:01:35Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-d8af6e23b4bc43b68061b3cd5ae0f3dd2023-05-07T11:17:46ZengNature PortfolioNature Communications2041-17232023-05-0114111610.1038/s41467-023-37567-wNeutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formationYafeng Li0Jessica S. Hook1Qing Ding2Xue Xiao3Stephen S. Chung4Marcel Mettlen5Lin Xu6Jessica G. Moreland7Michalis Agathocleous8Children’s Medical Center Research Institute, University of Texas Southwestern Medical CenterDepartment of Pediatrics, University of Texas Southwestern Medical CenterChildren’s Medical Center Research Institute, University of Texas Southwestern Medical CenterDepartment of Pediatrics, University of Texas Southwestern Medical CenterDepartment of Internal Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical CenterDepartment of Cell Biology, Quantitative Light Microscopy Core, University of Texas Southwestern Medical CenterDepartment of Pediatrics, University of Texas Southwestern Medical CenterDepartment of Pediatrics, University of Texas Southwestern Medical CenterChildren’s Medical Center Research Institute, University of Texas Southwestern Medical CenterAbstract 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.https://doi.org/10.1038/s41467-023-37567-w |
| spellingShingle | Yafeng Li Jessica S. Hook Qing Ding Xue Xiao Stephen S. Chung Marcel Mettlen Lin Xu Jessica G. Moreland Michalis Agathocleous Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation Nature Communications |
| title | Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation |
| title_full | Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation |
| title_fullStr | Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation |
| title_full_unstemmed | Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation |
| title_short | Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation |
| title_sort | neutrophil metabolomics in severe covid 19 reveal gapdh as a suppressor of neutrophil extracellular trap formation |
| url | https://doi.org/10.1038/s41467-023-37567-w |
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