Airway macrophage metabolic reprogramming during interstitial lung disease

Abstract

Airway macrophages (AM) play a key role during the pathogenesis of pulmonary fibrosis. The underlying metabolic alterations driving this phenotype however are little understood. The aim of this thesis was to investigate the metabolic phenotype of AMs during pulmonary fibrosis (PF), to identify factors, which influence the pathogenesis of PF and to investigate the role of the immune modulatory metabolite itaconate during PF. In chapter 3, AM metabolic phenotype was analysed in patients with idiopathic pulmonary fibrosis (IPF) or chronic hypersensitivity pneumonitis (CHP) compared to healthy controls. In IPF AMs increased gene expression of first half TCA cycle genes was detected, as well as a dependency on glycolysis to sustain a pro-fibrotic phenotype, while AMs from CHP patients highly increased glycolysis and OXPHOS utilisation and a more pro-inflammatory macrophages phenotype was observed. These results highlight the influence of the environment and identify distinct AM phenotypes in clinically similar IPF and CHP. Recent paradigm shifting studies have shown that two types of AMs exist in the lung and during the pathogenesis of PF. In chapter 4, the underlying metabolic phenotype of tissue-resident (Tr-AM) and monocyte-recruited AMs (Mo-AM) was investigated using the bleomycin mouse model, which showed an increased utilisation of OXPHOS in Tr-AM but not Mo-AM during peak fibrosis. In chapter 5, the role of immune modulatory metabolite itaconate was investigated during PF. Itaconate has been shown to regulate AM metabolic activity and is anti-inflammatory and anti-microbial, however its role in the context of fibrosis is unknown. Analysis of the metabolic phenotype of AMs from IPF patients indicated that there was decreased expression of ACOD1, a gene which controls the synthesis of itaconate. Furthermore, Acod1-/- mice had more severe fibrosis compared to WT mice in bleomycin models, suggesting an anti-fibrotic role for itaconate. Ultimately, fibrosis was ameliorated by treatment with inhaled itaconate or adoptive transfer of itaconate-expressing Mo-AMs. Collectively, these findings reveal underlying metabolic programmes driving AM phenotype during pulmonary fibrosis and identify new therapeutic targets.