IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-37567-w.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-37567-w
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-37567-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Nan Xiao & Meng Nie & Huanhuan Pang & Bohong Wang & Jieli Hu & Xiangjun Meng & Ke Li & Xiaorong Ran & Quanxin Long & Haijun Deng & Na Chen & Shao Li & Ni Tang & Ailong Huang & Zeping Hu, 2021. "Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Lijing Kang & Huilin Yu & Xing Yang & Yuanbo Zhu & Xiaofei Bai & Ranran Wang & Yongliang Cao & Haochen Xu & Haiyu Luo & Lu Lu & Mei-Juan Shi & Yujing Tian & Wenying Fan & Bing-Qiao Zhao, 2020. "Neutrophil extracellular traps released by neutrophils impair revascularization and vascular remodeling after stroke," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    3. Emer P. Reeves & Hui Lu & Hugues Lortat Jacobs & Carlo G. M. Messina & Steve Bolsover & Giorgio Gabella & Eric O. Potma & Alice Warley & Jürgen Roes & Anthony W. Segal, 2002. "Killing activity of neutrophils is mediated through activation of proteases by K+ flux," Nature, Nature, vol. 416(6878), pages 291-297, March.
    4. Alpaslan Tasdogan & Brandon Faubert & Vijayashree Ramesh & Jessalyn M. Ubellacker & Bo Shen & Ashley Solmonson & Malea M. Murphy & Zhimin Gu & Wen Gu & Misty Martin & Stacy Y. Kasitinon & Travis Vande, 2020. "Metabolic heterogeneity confers differences in melanoma metastatic potential," Nature, Nature, vol. 577(7788), pages 115-120, January.
    5. Michalis Agathocleous & Corbin E. Meacham & Rebecca J. Burgess & Elena Piskounova & Zhiyu Zhao & Genevieve M. Crane & Brianna L. Cowin & Emily Bruner & Malea M. Murphy & Weina Chen & Gerald J. Spangru, 2017. "Ascorbate regulates haematopoietic stem cell function and leukaemogenesis," Nature, Nature, vol. 549(7673), pages 476-481, September.
    6. Peng Wu & Dongsheng Chen & Wencheng Ding & Ping Wu & Hongyan Hou & Yong Bai & Yuwen Zhou & Kezhen Li & Shunian Xiang & Panhong Liu & Jia Ju & Ensong Guo & Jia Liu & Bin Yang & Junpeng Fan & Liang He &, 2021. "The trans-omics landscape of COVID-19," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    7. Moritz Leppkes & Christian Maueröder & Sebastian Hirth & Stefanie Nowecki & Claudia Günther & Ulrike Billmeier & Susanne Paulus & Mona Biermann & Luis E. Munoz & Markus Hoffmann & Dane Wildner & Andre, 2016. "Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis," Nature Communications, Nature, vol. 7(1), pages 1-13, April.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Roman Thaler & Farzaneh Khani & Ines Sturmlechner & Sharareh S. Dehghani & Janet M. Denbeigh & Xianhu Zhou & Oksana Pichurin & Amel Dudakovic & Sofia S. Jerez & Jian Zhong & Jeong-Heon Lee & Ramesh Na, 2022. "Vitamin C epigenetically controls osteogenesis and bone mineralization," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Yongxian Hu & Jingjing Li & Fang Ni & Zhongli Yang & Xiaohua Gui & Zhiwei Bao & Houli Zhao & Guoqing Wei & Yiyun Wang & Mingming Zhang & Ruimin Hong & Linqin Wang & Wenjun Wu & Mohamad Mohty & Arnon N, 2022. "CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Zhiqiang Pang & Lei Xu & Charles Viau & Yao Lu & Reza Salavati & Niladri Basu & Jianguo Xia, 2024. "MetaboAnalystR 4.0: a unified LC-MS workflow for global metabolomics," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Yu-Jung Tseng & Yuki Kageyama & Rebecca L. Murdaugh & Ayumi Kitano & Jong Hwan Kim & Kevin A. Hoegenauer & Jonathan Tiessen & Mackenzie H. Smith & Hidetaka Uryu & Koichi Takahashi & James F. Martin & , 2024. "Increased iron uptake by splenic hematopoietic stem cells promotes TET2-dependent erythroid regeneration," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Hongwei Lv & Qianni Zong & Cian Chen & Guishuai Lv & Wei Xiang & Fuxue Xing & Guoqing Jiang & Bing Yan & Xiaoyan Sun & Yue Ma & Liang Wang & Zixin Wu & Xiuliang Cui & Hongyang Wang & Wen Yang, 2024. "TET2-mediated tumor cGAS triggers endothelial STING activation to regulate vasculature remodeling and anti-tumor immunity in liver cancer," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    6. Samuel Druzak & Elizabeth Iffrig & Blaine R. Roberts & Tiantian Zhang & Kirby S. Fibben & Yumiko Sakurai & Hans P. Verkerke & Christina A. Rostad & Ann Chahroudi & Frank Schneider & Andrew Kam Ho Wong, 2023. "Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    7. Guanqun Li & Liwei Liu & Tianqi Lu & Yuhang Sui & Can Zhang & Yongwei Wang & Tao Zhang & Yu Xie & Peng Xiao & Zhongjie Zhao & Chundong Cheng & Jisheng Hu & Hongze Chen & Dongbo Xue & Hua Chen & Gang W, 2023. "Gut microbiota aggravates neutrophil extracellular traps-induced pancreatic injury in hypertriglyceridemic pancreatitis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    8. Morten Tulstrup & Mette Soerensen & Jakob Werner Hansen & Linn Gillberg & Maria Needhamsen & Katja Kaastrup & Kristian Helin & Kaare Christensen & Joachim Weischenfeldt & Kirsten Grønbæk, 2021. "TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    9. Lin Lin & Zhaojing Ba & Hao Tian & Haoxiang Qin & Xi Chen & Xin Zhou & Shanlan Zhao & Lang Li & Fangchao Xue & Hong Li & Lang He & Xiaochen Li & Jiahui Du & Zhenhua Zhou & Wen Zeng, 2024. "Ultrasound-responsive theranostic platform for the timely monitoring and efficient thrombolysis in thrombi of tPA resistance," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37567-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.