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. LundbladMatthew E. Poynter, Anne E. Dixon, Charles G. Irvin, Albert van der Vliet, Jos L. van der Velden, Yvonne M. Janssen-Heininger

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Abstract

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.

Original languageEnglish
Article number102160
Number of pages11
JournalRedox Biology
Volume47
Early online date3 Oct 2021
DOIs
Publication statusPublished - Nov 2021

Keywords

  • Allergic airways disease
  • House dust mite
  • Interleukin-1β
  • S-glutathionylation
  • Thymic stromal lymphopoietin

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