Dysregulation of Pyruvate Kinase M2 Promotes Inflammation in a Mouse Model of Obese Allergic Asthma

Abstract

Obesity is a risk factor for the development of asthma and represents a difficult-to-treat disease phenotype. Aerobic glycolysis is emerging as a key feature of asthma, and changes in glucose metabolism are linked to leukocyte activation and adaptation to oxidative stress. Dysregulation of PKM2 (pyruvate kinase M2), the enzyme that catalyzes the last step of glycolysis, contributes to house dust mite (HDM)-induced airway inflammation and remodeling in lean mice. It remains unclear whether glycolytic reprogramming and dysregulation of PKM2 also contribute to obese asthma. The goal of the present study was to elucidate the functional role of PKM2 in a murine model of obese allergic asthma. We evaluated the small molecule activator of PKM2, TEPP46, and assessed the role of PKM2 using conditional ablation of the Pkm2 allele from airway epithelial cells. In obese C57BL/6NJ mice, parameters indicative of glycolytic reprogramming remained unchanged in the absence of stimulation with HDM. Obese mice that were subjected to HDM showed evidence of glycolytic reprogramming, and treatment with TEPP46 diminished airway inflammation, whereas parameters of airway remodeling were unaffected. Epithelial ablation of Pkm2 decreased central airway resistance in both lean and obese allergic mice in addition to decreasing inflammatory cytokines in the lung tissue. Lastly, we highlight a novel role for PKM2 in the regulation of glutathione-dependent protein oxidation in the lung tissue of obese allergic mice via a putative IFN-g-glutaredoxin1 pathway. Overall, targeting metabolism and protein oxidation may be a novel treatment strategy for obese allergic asthma.

Immune Metabolism in TH2 Responses: New Opportunities to Improve Allergy Treatment — Disease-Specific Findings (Part 1)

“…Their results were independently confirmed by Manuel et al, who showed HDM to trigger PKM2-dependent glycolytic reprogramming and airway inflammation in a murine model of obese allergic asthma and airway epithelial cells [ 38 ]. These results suggest alternative, non-glycolytic functions of PKM2 to exert pro-inflammatory roles in asthma by glutathione-dependent protein oxidation via a putative IFN-γ–glutaredoxin 1 pathway [ 38 ].…”

“…Asthma is a complex disease comprising different phenotypes that are characterized by airway-inflammation, -remodeling, and -hyperreactivity. Studies have repeatedly shown the presence of metabolic anomalies in asthmatic patients and many metabolic pathways, including glycolysis [36][37][38][39][40], amino acid metabolism [41,42], fatty acid metabolism [43,44], and sphingosine metabolism [45][46][47],…”

Emerging roles of SIRT1 activator, SRT2104, in disease treatment

“…Moreover, recent insights suggest SRT2104's anti-inflammatory effects may be partially attributed to modulating pyruvate kinase M2 (PKM2), a key inflammatory regulator in conditions such as sepsis, asthma, and encephalomyelitis. Elevated PKM2 levels during inflammation can be counteracted by autophagy [118][119][120] , highlighting another potential mechanism for SRT2104's therapeutic action.…”

Sirtuin 1 activator alleviated lethal inflammatory injury via promotion of autophagic degradation of pyruvate kinase M2

“…A growing body of evidence suggests that metabolic reprogramming would be actively involved in the orchestration of metabolic processes and inflammatory responses under various pathological circumstance including critical illness, metabolic syndrome, tumor, et al ( Mazumdar et al, 2020 ). Pyruvate kinase M2 (PKM2), a key enzyme in the last step of glycolysis, has been regarded as a crucial regulator in inflammatory diseases such as sepsis, asthma as well as encephalomyelitis ( Yang et al, 2014 ; Damasceno et al, 2020 ; Manuel et al, 2021 ). PKM2 is significantly upregulated in inflammatory response, which promotes the expression of pro-inflammatory genes via a diverse of mechanisms ( Yang et al, 2014 ; Palsson-McDermott et al, 2015 ).…”