Description

Itaconate regulates responses to inhaled aeroallergen

Gesa J. Albers1, Patricia P. Ogger1, Simone A. Walker1, John M. Halket2, Robert Gray2, Clare M. Lloyd1, Adam Byrne1
1National Heart and Lung Institute, Imperial College London, UK
2Mass Spectrometry Facility, King’s College London, UK

Background: Asthma is a chronic disease characterised by airway remodelling and hyperresponsiveness, mucus production and inflammation. Airway macrophages (AMs) are key sentinels of lung homeostasis and form the first line of defence against inhaled allergen. Increasing evidence suggests that changes in AM phenotype are underpinned by alterations in AM metabolism. The TCA cycle-derived metabolite itaconic acid (IA), synthesised by the enzyme aconitate decarboxylase (ACOD)-1, is a key regulator of macrophage function. Recently, we showed in human and murine models that IA limits pulmonary fibrosis, yet its role in regulating pulmonary responses to inhaled allergen is unknown. Here, we aimed to study the role of IA in murine models of allergic airway disease (AAD).
Methods: To characterise the kinetics of the Acod1/IA pathway in response to allergen, we measured lung Acod1 expression and BAL-IA levels after house dust mite (HDM) challenge. Next, we assessed Acod1 expression in murine AMs exposed to HDM ex vivo. Finally, to determine the role of IA in allergic airway responses, we treated WT or Acod1-/- mice with inhaled HDM and assessed disease pathology and inflammation.
Results: Continuous HDM exposure in mice resulted in augmented levels of BAL-IA and increased expression of lung Acod1. Ex vivo culture of AMs with HDM revealed enhanced Acod1 expression and a shift towards a more glycolytic phenotype. Finally, exposure of Acod1-/- mice to allergen led to an increased neutrophil-to-eosinophil ratio, compared to more eosinophilic WT controls, which was rescued by inhaled IA.
Conclusion: Our data indicate that the Acod1/IA pathway is highly induced during AAD and regulates the balance between neutrophil and eosinophil recruitment in response to inhaled allergen.