Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1−/− mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1−/− tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.

encompassed genes and pathways pertinent to macrophage biology and IPF pathogenesis. Importantly, epigenetic changes in genes involved in lipid and glucose metabolism were related to clinical features of IPF severity. Thus, our study establishes a link between the epigenome, AM metabolism and disease severity during IPF.

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Summary Interferon regulatory factor 5 (IRF5) is a master regulator of macrophage phenotype and a key transcription factor involved in expression of proinflammatory cytokine responses to microbial and viral infection. Here, we show that IRF5 controls cellular and metabolic responses. By integrating ChIP sequencing (ChIP‐Seq) and assay for transposase‐accessible chromatin using sequencing (ATAC)‐seq data sets, we found that IRF5 directly regulates metabolic genes such as hexokinase‐2 (Hk2). The interaction of IRF5 and metabolic genes had a functional consequence, as Irf5−/− airway macrophages but not bone marrow‐derived macrophages (BMDMs) were characterized by a quiescent metabolic phenotype at baseline and had reduced ability to utilize oxidative phosphorylation after Toll‐like receptor (TLR)‐3 activation, in comparison to controls, ex vivo. In a murine model of influenza infection, IRF5 deficiency had no effect on viral load in comparison to wild‐type controls but controlled metabolic responses to viral infection, as IRF5 deficiency led to reduced expression of Sirt6 and Hk2. Together, our data indicate that IRF5 is a key component of AM metabolic responses following influenza infection and TLR‐3 activation.

Extract Idiopathic pulmonary fibrosis (IPF) is a chronic debilitating lung disease, characterised by progressive deposition of excessive extracellular matrix in the lung parenchyma [ 1 ]. Though rare, IPF has a median untreated survival of 3 years from diagnosis, making it more deadly than many cancers [ 2 , 3 ]. Two antifibrotic therapies, pirfenidone and nintedanib, have been shown to effectively slow IPF progression, but neither stop or reverse fibrogenesis [ 3 ]. Thus, there is an urgent unmet clinical need to develop more effective treatments for IPF and identify biomarkers.

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Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, the epigenetics of AMs development and function in IPF are limited. Here, we characterised the DNA-methylation (DNAm) profile of AMs from IPF (n=30) and healthy (n=14) donors. Our analysis revealed epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm ‘clock’ analysis indicated epigenetic alterations in IPF-AMs was not associated with accelerated ageing. In differential DNAm analysis, we identified numerous differentially methylated positions (DMPs, n=11) and regions (DMRs, n=49) between healthy and IPF AMs respectively. DMPs and DMRs encompassed genes involved in lipid (LPCAT1) and glucose (PFKB3) metabolism and importantly, DNAm status was associated with disease severity in IPF. Collectively, our data identify that profound changes in the epigenome underpin the development and function of AMs in the IPF lung.

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