Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2
Cheryl van de Wetering,
Allison M. Manuel,
Mona Sharafi,
Reem Aboushousha,
Xi Qian,
Cuixia Erickson,
Maximilian MacPherson,
Garrett Chan,
Ian M. Adcock,
Nazanin ZounematKermani,
Florence Schleich,
Renaud Louis,
Eric Bohrnsen,
Angelo D'Alessandro,
Emiel F. Wouters,
Niki L. Reynaert,
Jianing Li,
C. Roland Wolf,
Colin J. Henderson,
Lennart K.A. Lundblad,
Matthew E. Poynter,
Anne E. Dixon,
Charles G. Irvin,
Albert van der Vliet,
Jos L. van der Velden,
Yvonne M. Janssen-Heininger
Affiliations
Cheryl van de Wetering
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
Allison M. Manuel
Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA
Mona Sharafi
Department of Chemistry, University of Vermont, Burlington, VT, USA
Reem Aboushousha
Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA
Xi Qian
Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA
Cuixia Erickson
Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA
Maximilian MacPherson
Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA
Garrett Chan
Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA
Ian M. Adcock
National Heart & Lung Institute & Data Science Institute, Imperial College London, UK
Nazanin ZounematKermani
National Heart & Lung Institute & Data Science Institute, Imperial College London, UK
Florence Schleich
Department of Respiratory Medicine, CHU Sart-TilmanB35, Liege, Belgium
Renaud Louis
Department of Respiratory Medicine, CHU Sart-TilmanB35, Liege, Belgium
Eric Bohrnsen
Department of Biochemistry and Molecular Genetics, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States
Angelo D'Alessandro
Department of Biochemistry and Molecular Genetics, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States
Emiel F. Wouters
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
Niki L. Reynaert
Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands
Jianing Li
Department of Chemistry, University of Vermont, Burlington, VT, USA
C. Roland Wolf
Systems Medicine, School of Medicine, University of Dundee, Jacqui Wood Cancer Center, Ninewells Hospital Dundee DD1 9SY, Scotland, United Kingdom
Colin J. Henderson
Systems Medicine, School of Medicine, University of Dundee, Jacqui Wood Cancer Center, Ninewells Hospital Dundee DD1 9SY, Scotland, United Kingdom
Lennart K.A. Lundblad
Meakins-Christie Laboratories, McGill University & THORASYS Thoracic Medical Systems Inc., Montréal, QC, Canada
Matthew E. Poynter
Department of Medicine, College of Medicine, University of Vermont, Burlington, VT, USA
Anne E. Dixon
Department of Medicine, College of Medicine, University of Vermont, Burlington, VT, USA
Charles G. Irvin
Department of Medicine, College of Medicine, University of Vermont, Burlington, VT, USA
Albert van der Vliet
Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA
Jos L. van der Velden
Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA
Yvonne M. Janssen-Heininger
Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA; Corresponding author. Department of Pathology and Laboratory Medicine, University of Vermont, HSRF Building, Room 216A. Burlington, VT, 05405, USA.
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.
