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

doi:10.1016/j.redox.2021.102160

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

Research output: Contribution to journal › Article › peer-review

44 Citations (Scopus)

285 Downloads (Pure)

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 language	English
Article number	102160
Number of pages	11
Journal	Redox Biology
Volume	47
Early online date	3 Oct 2021
DOIs	https://doi.org/10.1016/j.redox.2021.102160
Publication status	Published - Nov 2021

Keywords

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

ASJC Scopus subject areas

Organic Chemistry
Clinical Biochemistry

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van de Wetering, C., Manuel, A. M., Sharafi, M., Aboushousha, R., Qian, X., Erickson, C., MacPherson, M., Chan, G., Adcock, I. M., ZounematKermani, N., Schleich, F., Louis, R., Bohrnsen, E., D'Alessandro, A., Wouters, E. F., Reynaert, N. L., Li, J., Wolf, C. R., Henderson, C. J., ... Janssen-Heininger, Y. M. (2021). Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2. Redox Biology, 47, Article 102160. https://doi.org/10.1016/j.redox.2021.102160

@article{28ce8ac0fdd84cc7b0506719f4c43119,

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

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.",

keywords = "Allergic airways disease, House dust mite, Interleukin-1β, S-glutathionylation, Thymic stromal lymphopoietin",

author = "\{van de Wetering\}, Cheryl and Manuel, \{Allison M.\} and Mona Sharafi and Reem Aboushousha and Xi Qian and Cuixia Erickson and Maximilian MacPherson and Garrett Chan and Adcock, \{Ian M.\} and Nazanin ZounematKermani and Florence Schleich and Renaud Louis and Eric Bohrnsen and Angelo D'Alessandro and Wouters, \{Emiel F.\} and Reynaert, \{Niki L.\} and Jianing Li and Wolf, \{C. Roland\} and Henderson, \{Colin J.\} and Lundblad, \{Lennart K. A.\} and Poynter, \{Matthew E.\} and Dixon, \{Anne E.\} and Irvin, \{Charles G.\} and \{van der Vliet\}, Albert and \{van der Velden\}, \{Jos L.\} and Janssen-Heininger, \{Yvonne M.\}",

note = "Funding Information: 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{\textquoteright}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{\textendash}2013 ) and EFPIA companies' in-kind contribution ( www.imi.europa.eu ). The computational resources were provided by the Vermont Advanced Computer Core. Funding Information: 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. Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = nov,

doi = "10.1016/j.redox.2021.102160",

language = "English",

volume = "47",

journal = "Redox Biology",

issn = "2213-2317",

publisher = "Elsevier",

}

van de Wetering, C, Manuel, AM, Sharafi, M, Aboushousha, R, Qian, X, Erickson, C, MacPherson, M, Chan, G, Adcock, IM, ZounematKermani, N, Schleich, F, Louis, R, Bohrnsen, E, D'Alessandro, A, Wouters, EF, Reynaert, NL, Li, J, Wolf, CR , Henderson, CJ, Lundblad, LKA, Poynter, ME, Dixon, AE, Irvin, CG, van der Vliet, A, van der Velden, JL & Janssen-Heininger, YM 2021, 'Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2', Redox Biology, vol. 47, 102160. https://doi.org/10.1016/j.redox.2021.102160

TY - JOUR

T1 - Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2

AU - van de Wetering, Cheryl

AU - Manuel, Allison M.

AU - Sharafi, Mona

AU - Aboushousha, Reem

AU - Qian, Xi

AU - Erickson, Cuixia

AU - MacPherson, Maximilian

AU - Chan, Garrett

AU - Adcock, Ian M.

AU - ZounematKermani, Nazanin

AU - Schleich, Florence

AU - Louis, Renaud

AU - Bohrnsen, Eric

AU - D'Alessandro, Angelo

AU - Wouters, Emiel F.

AU - Reynaert, Niki L.

AU - Li, Jianing

AU - Wolf, C. Roland

AU - Henderson, Colin J.

AU - Lundblad, Lennart K. A.

AU - Poynter, Matthew E.

AU - Dixon, Anne E.

AU - Irvin, Charles G.

AU - van der Vliet, Albert

AU - van der Velden, Jos L.

AU - Janssen-Heininger, Yvonne M.

N1 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2021

PY - 2021/11

Y1 - 2021/11

N2 - 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.

AB - 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.

KW - Allergic airways disease

KW - House dust mite

KW - Interleukin-1β

KW - S-glutathionylation

KW - Thymic stromal lymphopoietin

UR - https://www.scopus.com/pages/publications/85116398753

U2 - 10.1016/j.redox.2021.102160

DO - 10.1016/j.redox.2021.102160

M3 - Article

C2 - 34624602

SN - 2213-2317

VL - 47

JO - Redox Biology

JF - Redox Biology

M1 - 102160

ER -

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

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