Dexamethasone protects against Aspergillus fumigatus-induced severe asthma via modulating pulmonary immunometabolism

Phyllis X L Gan; Wupeng Liao; Hui Fang Lim; W S Fred Wong

doi:10.1016/j.phrs.2023.106929

Dexamethasone protects against Aspergillus fumigatus-induced severe asthma via modulating pulmonary immunometabolism

Pharmacol Res. 2023 Oct:196:106929. doi: 10.1016/j.phrs.2023.106929. Epub 2023 Sep 15.

Authors

Phyllis X L Gan¹, Wupeng Liao², Hui Fang Lim³, W S Fred Wong⁴

Affiliations

¹ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
² Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Singapore-HUJ Alliance for Research and Enterprise, National University of Singapore, Singapore.
³ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Respiratory and Critical Care Medicine, Department of Medicine, National University Hospital, National University Health System, Singapore.
⁴ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Singapore-HUJ Alliance for Research and Enterprise, National University of Singapore, Singapore; Drug Discovery & Optimization Platform, Yong Loo Lin School of Medicine, National University Health System, Singapore. Electronic address: phcwongf@nus.edu.sg.

PMID: 37717682
DOI: 10.1016/j.phrs.2023.106929

Abstract

Severe asthma is a difficult-to-treat chronic airway inflammatory disease requiring systemic corticosteroids to achieve asthma control. It has recently been shown that drugs targeting immunometabolism have elicited anti-inflammatory effects. The purpose of this study was to investigate potential immunometabolic modulatory actions of systemic dexamethasone (Dex) in an Aspergillus fumigatus (Af)-induced severe asthma model. Mice were repeatedly exposed to the Af aeroallergen before systemic treatment with Dex. Simultaneous measurements of airway inflammation, real-time glycolytic and oxidative phosphorylation (OXPHOS) activities, expression levels of key metabolic enzymes, and amounts of metabolites were studied in lung tissues, and in primary alveolar macrophages (AMs) and eosinophils. Dex markedly reduced Af-induced eosinophilic airway inflammation, which was coupled with an overall reduction in lung glycolysis, glutaminolysis, and fatty acid synthesis. The anti-inflammatory effects of Dex may stem from its immunometabolic actions by downregulating key metabolic enzymes including pyruvate dehydrogenase kinase, glutaminase, and fatty acid synthase. Substantial suppression of eosinophilic airway inflammation by Dex coincided with a specific escalation of mitochondrial proton leak in primary lung eosinophils. Besides, while our findings confirmed that inflammation corresponds with an upregulation of glycolysis, it was accompanied with an unexpectedly stable or elevated OXPHOS in the lungs and activated immune cells, respectively. Our findings reveal that the anti-inflammatory effects of Dex in severe asthma are associated with downregulation of pyruvate dehydrogenase kinase, glutaminase, and fatty acid synthase, and the augmentation of mitochondrial proton leak in lung eosinophils. These enzymes and biological processes may be valuable targets for therapeutic interventions against severe asthma.

Keywords: Alveolar macrophages; Corticosteroid; Eosinophils; Inflammation; Metabolic reprogramming.