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

Autor:	van de Wetering C; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA; Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands., Manuel AM; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA., Sharafi M; Department of Chemistry, University of Vermont, Burlington, VT, USA., Aboushousha R; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA., Qian X; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA., Erickson C; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA., MacPherson M; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA., Chan G; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA., Adcock IM; National Heart & Lung Institute & Data Science Institute, Imperial College London, UK., ZounematKermani N; National Heart & Lung Institute & Data Science Institute, Imperial College London, UK., Schleich F; Department of Respiratory Medicine, CHU Sart-TilmanB35, Liege, Belgium., Louis R; Department of Respiratory Medicine, CHU Sart-TilmanB35, Liege, Belgium., Bohrnsen E; Department of Biochemistry and Molecular Genetics, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States., D'Alessandro A; Department of Biochemistry and Molecular Genetics, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States., Wouters EF; Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands; Ludwig Boltzmann Institute for Lung Health, Vienna, Austria., Reynaert NL; Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands., Li J; Department of Chemistry, University of Vermont, Burlington, VT, USA., Wolf CR; Systems Medicine, School of Medicine, University of Dundee, Jacqui Wood Cancer Center, Ninewells Hospital Dundee DD1 9SY, Scotland, United Kingdom., Henderson CJ; Systems Medicine, School of Medicine, University of Dundee, Jacqui Wood Cancer Center, Ninewells Hospital Dundee DD1 9SY, Scotland, United Kingdom., Lundblad LKA; Meakins-Christie Laboratories, McGill University & THORASYS Thoracic Medical Systems Inc., Montréal, QC, Canada., Poynter ME; Department of Medicine, College of Medicine, University of Vermont, Burlington, VT, USA., Dixon AE; Department of Medicine, College of Medicine, University of Vermont, Burlington, VT, USA., Irvin CG; Department of Medicine, College of Medicine, University of Vermont, Burlington, VT, USA., van der Vliet A; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA., van der Velden JL; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA., Janssen-Heininger YM; Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA. Electronic address: yvonne.janssen@uvm.edu.
Jazyk:	angličtina
Zdroj:	Redox biology [Redox Biol] 2021 Nov; Vol. 47, pp. 102160. Date of Electronic Publication: 2021 Oct 03.
DOI:	10.1016/j.redox.2021.102160
Abstrakt:	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. 13 C-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. (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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