Itaconate regulates responses to inhaled aeroallergen

Background: Asthma is a chronic disease of the airways characterised by airway remodelling, inflammation and mucus production. Airway macrophages (AMs) form a first line of defence against inhaled pathogen. In steady state and in response to pathogen, AM phenotype and function are underpinned by changes in cellular metabolism. The TCA cycle-derived metabolite itaconic acid (IA), synthesised by the enzyme aconitate decarboxylase (ACOD)-1, is a master regulator of macrophage function. We recently showed that IA limits pulmonary fibrosis in human and in murine models. However, its role in regulating asthma and allergic airway disease (AAD) is unknown. Methods: To study the kinetics of the Acod1/IA pathway in AAD, we analysed the metabolic profile of AMs ex vivo cultured with the aeroallergen house dust mite (HDM). Next, we measured airway inflammation, lung function and bronchoalveolar lavage (BAL) metabolite levels in WT and Acod1-/- mice. Finally, to investigate the role of IA in asthma, we measured metabolite levels in response to allergen challenge in sputum of mild asthmatics. Results:Ex vivo culture of AMs with HDM resulted in increased Acod1 expression and a more glycolytic phenotype. Continuous HDM exposure of WT mice led to increased lung Acod1 expression accompanied by augmented IA levels in BAL. Upon exposure to aeroallergen Acod1-/- mice showed a lower eosinophil-to-neutrophil ratio compared to more eosinophilic WT controls, which was rescued by inhaled IA. Finally, analysis of sputum from people with mild asthma revealed an inverse relationship between neutrophil numbers and IA levels. 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.