Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2

Allergic airways disease; House dust mite; Interleukin-1β; S-glutathionylation; Thymic stromal lymphopoietin; glutathione transferase P; interleukin 1beta; lactic acid; pyruvate kinase; pyruvate kinase M2; transferase; unclassified drug; glutathione; glutathione transferase; allergic reaction; animal cell; animal experiment; animal model; Article; asthma; C57BL 6 mouse; clinical article; controlled study; Dermatophagoides; disease severity; enzyme metabolism; glycolysis; human; inflammation; metabolomics; mouse; nonhuman; pathogenesis; proteomics; respiratory tract allergy; transcriptomics; animal; genetics; lung; metabolism; Animals; Asthma; Glutathione; Glutathione Transferase; Glycolysis; Lung; Mice; Pyruvate Kinase

Abstract :

[en] Background: Interleukin-1-dependent increases in glycolysis promote allergic airways disease in mice and disruption of pyruvate kinase M2 (PKM2) activity is critical herein. Glutathione-S-transferase P (GSTP) has been implicated in asthma pathogenesis and regulates the oxidation state of proteins via S-glutathionylation. We addressed whether GSTP-dependent S-glutathionylation promotes allergic airways disease by promoting glycolytic reprogramming and whether it involves the disruption of PKM2. Methods: We used house dust mite (HDM) or interleukin-1β in C57BL6/NJ WT or mice that lack GSTP. Airway basal cells were stimulated with interleukin-1β and the selective GSTP inhibitor, TLK199. GSTP and PKM2 were evaluated in sputum samples of asthmatics and healthy controls and incorporated analysis of the U-BIOPRED severe asthma cohort database. Results: Ablation of Gstp decreased total S-glutathionylation and attenuated HDM-induced allergic airways disease and interleukin-1β-mediated inflammation. Gstp deletion or inhibition by TLK199 decreased the interleukin-1β-stimulated secretion of pro-inflammatory mediators and lactate by epithelial cells. 13C-glucose metabolomics showed decreased glycolysis flux at the pyruvate kinase step in response to TLK199. GSTP and PKM2 levels were increased in BAL of HDM-exposed mice as well as in sputum of asthmatics compared to controls. Sputum proteomics and transcriptomics revealed strong correlations between GSTP, PKM2, and the glycolysis pathway in asthma. Conclusions: GSTP contributes to the pathogenesis of allergic airways disease in association with enhanced glycolysis and oxidative disruption of PKM2. Our findings also suggest a PKM2-GSTP-glycolysis signature in asthma that is associated with severe disease. © 2021

Disciplines :

Cardiovascular & respiratory systems

Author, co-author :

van de Wetering, C.; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, United States, Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Netherlands

Manuel, A.M.; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, United States

Sharafi, M.; Department of Chemistry, University of Vermont, Burlington, VT, United States

Aboushousha, R.; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, United States

Qian, X.; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, United States

Erickson, C.; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, United States

MacPherson, M.; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, United States

Chan, G.; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, United States

Adcock, I.M.; National Heart & Lung Institute & Data Science Institute, Imperial College LondonUK, United Kingdom

ZounematKermani, N.; National Heart & Lung Institute & Data Science Institute, Imperial College LondonUK, United Kingdom

More authors (16 more)

Language :

English

Title :

Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2

Publication date :

2021

Journal title :

Redox Biology

eISSN :

2213-2317

Publisher :

Elsevier B.V.

Volume :

Peer reviewed :

Peer Reviewed verified by ORBi

Funding text :

This work was supported by grants NIH R01 HL137268 , R35HL135828 (Y-JH), an unrestricted grant from Chiesi (EW) , and Cancer Center Support Grant P30CA046934 (AD’A). We acknowledge the technical expertise of J. Bates, N. Daphtary and M. Aliyeva with AHR analysis. Imaging was performed in the Microscopy Imaging Center at the University of Vermont (RRID# SCR_018821 ), and we also acknowledge the Larner College of Medicine Shared Instrumentation Award. U-BIOPRED was supported by an Innovative Medicines Initiative Joint Undertaking (No. 115010 ), resources from the European Union's Seventh Framework Programme ( FP7/2007–2013 ) and EFPIA companies' in-kind contribution ( www.imi.europa.eu ). The computational resources were provided by the Vermont Advanced Computer Core.

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