Itaconate controls the severity of pulmonary fibrosis.

Abstract

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.

• Authors: Patricia P Ogger, Gesa J Albers, Richard J Hewitt, Brendan J O'Sullivan, Joseph E Powell, Emily Calamita, Poonam Ghai, Simone A Walker, Peter McErlean, Peter Saunders, Shaun Kingston, Philip L Molyneaux, John M Halket, Robert Gray, Daniel C Chambers, Toby M Maher, Clare M Lloyd, Adam J Byrne
• Journal: Science immunology (Sci Immunol) Vol. 5 Issue 52 (Oct 23 2020) ISSN: 2470-9468 [Electronic] United States
• PMID: 33097591 (Publication Type: Journal Article, Observational Study, Research Support, Non-U.S. Gov't)

Chemical References

• Succinates
• Bleomycin
• ACOD1 protein, human
• Carboxy-Lyases
• Hydro-Lyases
• Irg1 protein, mouse
• itaconic acid

Topics

• Administration, Inhalation
• Adoptive Transfer (methods)
• Adult
• Aged
• Animals
• Bleomycin (administration & dosage, toxicity)
• Bronchoalveolar Lavage Fluid (immunology)
• Bronchoscopy
• Carboxy-Lyases (metabolism)
• Case-Control Studies
• Cells, Cultured
• Disease Models, Animal
• Female
• Fibroblasts
• Healthy Volunteers
• Humans
• Hydro-Lyases (genetics, metabolism)
• Idiopathic Pulmonary Fibrosis (chemically induced, diagnosis, immunology, therapy)
• Lung (cytology, immunology, pathology)
• Macrophages, Alveolar (immunology, metabolism, transplantation)
• Male
• Mice
• Mice, Knockout
• Middle Aged
• Primary Cell Culture
• Severity of Illness Index
• Succinates (administration & dosage, immunology, metabolism)