Mitochondrial dysfunction of eosinophils as a driving force for its activation in severe eosinophilic asthma
File(s)
Author(s)
Koranteng, Janice Beatrice Antwiwaa
Type
Thesis
Abstract
Severe eosinophilic asthma is a respiratory disease characterised by an increased number of blood and airway eosinophils and reversible airflow obstruction. Eosinophils contribute to the inflammation, airway remodelling, and bronchial damage observed in the lungs of asthmatics through the release of cationic proteins, cytokines and lipid mediators. Mitochondrial dysfunction has been identified in epithelial cells, airway smooth muscle cells and peripheral blood mononuclear cells from asthmatics. The role of mitochondrial dysfunction in eosinophils in severe eosinophilic asthma is incomplete, with significant gaps which need addressing in order to advance the field. I hypothesised that eosinophils from severe eosinophilic asthmatics display mitochondrial dysfunction, which contributes to their abnormal activation and survival. In this study, I show that eosinophils from severe eosinophilic asthmatics display altered mitochondrial function, with increased basal mitochondrial respiration, adenosine triphosphate (ATP) production, non-mitochondrial and maximal respiration, spare respiratory capacity and glycolytic activity, at baseline, compared to eosinophils from healthy volunteers, mild-moderate asthmatics and eosinophils that remain in severe eosinophilic asthmatics after mepolizumab treatment. Cytokines Interleukin (IL)-5 and granulocyte macrophage colony-stimulating factor (GM-CSF) increased eosinophil bioenergetics, whilst some eosinophils that remain after mepolizumab treatment were less responsive to the cytokines. IL-5 increased proton leak and led towards reduced mitochondrial membrane potential. I also demonstrate that eosinophils from severe eosinophilic asthmatics show a trend towards increased survival at baseline and is enhanced in response to IL-5. The pro-survival effect of IL-5 is dependent on mitochondrial and glycolytic pathways particularly in eosinophils from healthy volunteers, whilst severe eosinophilic asthma eosinophils show a possible mechanism of adaptive reprogramming to maintain their survival. Transcriptomic analysis showed that eosinophils from severe eosinophilic asthmatics show an upregulation in antioxidant pathways and downregulation in antiviral mechanisms. Metabolic reprogramming of eosinophils from severe eosinophilic asthmatics may therefore drive their increased persistence and altered function in disease.
Version
Open Access
Date Issued
2024-09-20
Date Awarded
2025-04-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Bhavsar, Pankaj
Chung, Kian Fan
Michaeloudes, Charalambos
Sponsor
National Heart and Lung Institute
GlaxoSmithKline
Grant Number
P82746
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)