Dexamethasone protects against asthma via regulating Hif-1α-glycolysis-lactate axis and protein lactylation

Chen N, Xie QM, Song SM, Guo SN, Fang Y, Fei GH, Wu HM.  Int Immunopharmacol. 2024 Mar 8;131:111791. doi: 10.1016/j.intimp.2024.111791. 

Abstract

Purpose

Asthma can not be eradicated till now and its control primarily relies on the application of corticosteroids. Recently, glycolytic reprogramming has been reportedly contributed to asthma, this study aimed to reveal whether the effect of corticosteroids on asthma control is related to their regulation of glycolysis and glycolysis-dependent protein lactylation.

Methods

Ovalbumin (OVA) aeroallergen was used to challenge mice and stimulate human macrophage cell line THP-1 following dexamethasone (DEX) treatment. Airway hyperresponsiveness, airway inflammation, the expressions of key glycolytic enzymes and pyroptosis markers, the level of lactic acid, real-time glycolysis and oxidative phosphorylation (OXPHOS), and protein lactylation were analyzed.

Results

DEX significantly attenuated OVA-induced eosinophilic airway inflammation, including airway hyperresponsiveness, leukocyte infiltration, goblet cell hyperplasia, Th2 cytokines production and pyroptosis markers expression. Meanwhile, OVA-induced Hif-1α-glycolysis axis was substantially downregulated by DEX, which resulted in low level of lactic acid. Besides, key glycolytic enzymes in the lungs of asthmatic mice were notably co-localized with F4/80-positive macrophages, indicating metabolic shift to glycolysis in lung macrophages during asthma. This was confirmed in OVA-stimulated THP-1 cells that DEX treatment resulted in reductions in pyroptosis, glycolysis and lactic acid level. Finally, protein lactylation was found significantly increased in the lungs of asthmatic mice and OVA-stimulated THP-1 cells, which were both inhibited by DEX.

Conclusion

Our present study revealed that the effect of DEX on asthma control was associated with its suppressing of Hif-1α-glycolysis-lactate axis and subsequent protein lactylation, which may open new avenues for the therapy of eosinophilic asthma.

Highlights

• Hif-1α-glycolysis and protein lactylation are increased in asthmatic mice.
• DEX attenuates OVA-induced Hif-1α-glycolysis and pyroptosis in vivo and in vitro.
• DEX suppresses OVA-induced protein lactylation in vivo and in vitro.