How does airway macrophage glycolytic reprogramming contribute to fibrotic lung disease?

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease and is associated with high mortality. IPF therapies are limited and there is a significant need to understand the mechanisms involved. Airway macrophages (AMs) are the most abundant immune cell in patients with IPF. Recent work demonstrated that IPF-AMs are characterised by high expression of glucose transport molecules but it is unknown whether AM-glycolytic programming contributes to the pathogenesis of lung fibrosis.

My preliminary data indicates that IPF-AMs have a unique metabolic phenotype, characterised by reduced succinate and elevated Irg1 expression, a negative regulator of the citric acid cycle via itaconic acid. I hypothesise that AM glycolytic reprogramming contributes to the pathogenesis of lung fibrosis and manipulation of AM metabolism via itaconic acid, and can ameliorate the disease. I will determine AM metabolic signatures in the fibrotic lung using metabolic assays in IPF-AMs and murine models. Then I will assess Irg1 and itaconic acid levels in patients’ broncoalveolar lavage (BAL)/lung biopsies. I will use siRNA knockdown in IPF-AMs and Irg1-/- mice.

This work will provide proof of principle for development of therapies which correct AM-metabolic dysregulation during IPF.