LAUSR

Asthma is a chronic lung disease characterized by airway remodeling, airway hyperresponsivenss and inflammation. Alterations in metabolism and associated changes in redox homeostasis have been shown to be an important feature of chronic lung diseases including asthma. Glutathione-S-transferase P (GSTP) catalyzes the forward protein S-glutathionylation (PSSG) reaction, thereby changing protein function. We recently demonstrated that IL1-dependent glycolysis contributes to house dust mite (HDM)-induced allergic airways disease resulting in enhanced inflammation. The goal of the present study was to determine whether GSTP-linked PSSG regulates glycolysis and controls allergic airways disease. Absence of Gstp attenuates the HDM-dependent increases in airway remodeling, sub epithelial fibrosis, airway hyperresponsiveness, and lactate. The HDM-mediated increases in PSSG were attenuated in Gstp-/- mice, and redox proteomics indicated increases in PSSG of pyruvate kinase M2 (PKM2-SSG) in HDM-exposed lungs. Direct exposure of recombinant PKM2 to GSSG, a condition that induces PSSG, resulted in a loss of its enzymatic activity. PKM2 activation as well as GSTP inhibition decreased the HDM- and/or IL-1s-induced inflammatory effect, and also attenuated the expression of phosphorylation of signal transducer and activator of transcription 3 (STAT3) in lungs and epithelial cells. Interestingly, STAT3 inhibition also attenuated the IL-1s-induced release of pro-inflammatory mediators. Overall, these results suggest the importance of GSTP-controlled S-glutathionylation chemisty in HDM-induced allergic airways disease in the promotion of IL-1s-induced inflammation and the alteration of metabolism in epithelial cells.