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

Autor: Chen N; Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, Anhui 230022, PR China; Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, Jixi Road 218, Hefei, Anhui 230022, PR China; Key Laboratory of Geriatric Molecular Medicine of Anhui Province, Jixi Road No. 218, Hefei, Anhui 230022, PR China., Xie QM; Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, Anhui 230022, PR China; Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, Jixi Road 218, Hefei, Anhui 230022, PR China; Key Laboratory of Geriatric Molecular Medicine of Anhui Province, Jixi Road No. 218, Hefei, Anhui 230022, PR China., Song SM; Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, Anhui 230022, PR China; Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, Jixi Road 218, Hefei, Anhui 230022, PR China; Key Laboratory of Geriatric Molecular Medicine of Anhui Province, Jixi Road No. 218, Hefei, Anhui 230022, PR China., Guo SN; Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, Anhui 230022, PR China; Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, Jixi Road 218, Hefei, Anhui 230022, PR China; Key Laboratory of Geriatric Molecular Medicine of Anhui Province, Jixi Road No. 218, Hefei, Anhui 230022, PR China., Fang Y; Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, Anhui 230022, PR China; Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, Jixi Road 218, Hefei, Anhui 230022, PR China; Key Laboratory of Geriatric Molecular Medicine of Anhui Province, Jixi Road No. 218, Hefei, Anhui 230022, PR China., Fei GH; Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, Jixi Road 218, Hefei, Anhui 230022, PR China; Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, Anhui 230022, PR China. Electronic address: gh.fei@ahmu.edu.cn., Wu HM; Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, Anhui 230022, PR China; Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, Jixi Road 218, Hefei, Anhui 230022, PR China; Key Laboratory of Geriatric Molecular Medicine of Anhui Province, Jixi Road No. 218, Hefei, Anhui 230022, PR China. Electronic address: wuhm@ahmu.edu.cn.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2024 Apr 20; Vol. 131, pp. 111791. Date of Electronic Publication: 2024 Mar 08.
DOI: 10.1016/j.intimp.2024.111791
Abstrakt: 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-lactateaxis and subsequent protein lactylation, which may open new avenues for the therapy of eosinophilic asthma.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: