Itaconate controls the severity of pulmonary fibrosis
| Autor: | Toby M. Maher, Brendan O'Sullivan, Peter McErlean, Adam J. Byrne, John M. Halket, Peter Saunders, Shaun Kingston, Simone A. Walker, Joseph E. Powell, Philip L. Molyneaux, Robert Gray, Clare M. Lloyd, Daniel C. Chambers, Patricia P. Ogger, Emily Calamita, Poonam Ghai, Richard J. Hewitt, Gesa J. Albers |
|---|---|
| Přispěvatelé: | Asthma UK, Wellcome Trust, National Heart & Lung Institute Foundation |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Adoptive cell transfer Carboxy-Lyases Severity of Illness Index Idiopathic pulmonary fibrosis chemistry.chemical_compound Mice 0302 clinical medicine Fibrosis Pulmonary fibrosis Lung Cells Cultured Mice Knockout medicine.diagnostic_test General Medicine respiratory system Middle Aged Adoptive Transfer Healthy Volunteers medicine.anatomical_structure 030220 oncology & carcinogenesis Female Bronchoalveolar Lavage Fluid Adult Immunology Primary Cell Culture Bleomycin Article 03 medical and health sciences In vivo Administration Inhalation Bronchoscopy Macrophages Alveolar medicine Animals Humans Hydro-Lyases Aged business.industry Succinates Fibroblasts medicine.disease Idiopathic Pulmonary Fibrosis respiratory tract diseases Disease Models Animal 030104 developmental biology Bronchoalveolar lavage chemistry Case-Control Studies business |
| Zdroj: | Sci Immunol |
| ISSN: | 2470-9468 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|