Itaconate controls the severity of pulmonary fibrosis
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2020-10-23
Date Acceptance
2020-09-29
Citation
Science Immunology, 2020, 5 (52), pp.1-13
ISSN
2470-9468
Publisher
American Association for the Advancement of Science
Start Page
1
End Page
13
Journal / Book Title
Science Immunology
Volume
5
Issue
52
Copyright Statement
© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works https://www.sciencemag.org/about/science-licenses-journal-article-reuse. . This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Immunology on Volume 5, 23 Oct 2020. DOI: https://immunology.sciencemag.org/content/5/52/eabc1884
Sponsor
Asthma UK
Wellcome Trust
National Heart & Lung Institute Foundation
National Heart & Lung Institute Foundation
Asthma UK
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33097591
PII: 5/52/eabc1884
Grant Number
Asthma UK Centre
205949/Z/17/Z
CAD 2017-2023
Students 2016-19
AUK-SCF-2017-381
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2020-10-23