Asthma is a chronic condition of the airways with airway hyperresponsiveness (AHR),
inflammation and remodelling. Airway macrophages (AMs) are crucial during homeostasis and
inflammation. To maintain tolerance in the lungs, AMs can adapt their phenotype in
accordance with environmental cues. Changes in macrophage function are underpinned by
alterations in cellular metabolism. However, metabolic responses of AMs to aeroallergen have
not formally been established. The aim of this thesis was to understand AM metabolic
responses to allergen and how these influence allergic airway disease (AAD) pathology.
Metabolite levels were measured in the sputum of patients with mild asthma after allergen
challenge and in murine BAL following house dust mite (HDM) exposure. Upon allergen
challenge, patients with asthma had altered levels of lactate, as well as TCA cycle metabolites
itaconate, fumarate and malate. In mice, HDM drove the accumulation of lactate and itaconate,
indicative of a glycolytic environment.
HDM exposure in vivo or ex vivo resulted in AM metabolic reprogramming and acquisition of
a highly glycolytic phenotype. Inhibition of glycolysis in AMs ex vivo prevented HDM-driven
transcriptional changes. In addition, manipulation of the AM metabolic phenotype in vivo by
inhibition of the TCA cycle enzyme succinate dehydrogenase alleviated AHR.
Expression of aconitate decarboxylase-1 (Acod1), encoding the enzyme which synthesises
itaconate, was highly induced in murine AMs and lungs following HDM challenge and itaconate
accumulated in the airways. Acod1-deficiency did not affect the AAD phenotype at peak
inflammation and remodelling-dominated time points. However, Acod1 -/- mice displayed
reduced AHR and increased neutrophilia during resolution of AAD. In addition, administration
of exogenous itaconate resulted in alterations in neutrophil phenotype yet failed to affect AHR.
Collectively, this thesis shows that allergen exposure promotes a glycolytic AM phenotype and
pulmonary environment, and that manipulation of AM metabolism can reduce AHR, making it
a promising tool for AAD therapy.