Itaconate drives the resolution of pulmonary fibrosis

Abstract

Introduction a Objectives: Airway macrophages (AMs) are implicated in the dysregulated wound healing response in idiopathic pulmonary fibrosis (IPF). The endogenous metabolite itaconate, synthesised by immune-response gene 1 (IRG1), has been shown to influence macrophage function via regulation of succinate dehydrogenase. Here we investigated the role of itaconate in pulmonary fibrosis. Methods: To assess the expression pattern of Irg1 in the lung, we analysed gene expression in AMs from IPF patients or controls. To investigate the role of itaconate in the bleomycin model of pulmonary fibrosis we utilised WT and Irg1-/- mice, in addition to therapeutic dosing of exogenous itaconate. To determine the role of secreted itaconate on the stromal compartment in IPF, primary lung fibroblasts were cultured with itaconate in vitro and proliferation/wound healing was assessed. Results: Irg1 expression was reduced in IPF AMs compared to controls. In the bleomycin model, Irg1-/- mice had decreased survival, worsened lung function and increased collagen deposition at the resolution time point (42d post bleomycin). Tissue-resident AMs (Tr-AMs) upregulated the expression of fibrosis-related genes in Irg1-/- mice and showed impaired Oxidative Phosphorylation. Inhaled itaconate during the fibrotic phase of the bleomycin model improved lung function and decreased gene expression of type IV collagen and fibronectin. In vitro culture of primary human lung fibroblasts with itaconate decreased proliferation and wound healing capacity. Conclusions: Overall these data indicate that itaconate is essential for the resolution of lung fibrosis and that targeting this pathway may be a viable therapeutic strategy in IPF.