RT Journal Article
SR Electronic
T1 Itaconate controls the severity of pulmonary fibrosis
JF Science Immunology
JO Sci. Immunol.
FD American Association for the Advancement of Science
SP eabc1884
DO 10.1126/sciimmunol.abc1884
VO 5
IS 52
A1 Ogger, Patricia P.
A1 Albers, Gesa J.
A1 Hewitt, Richard J.
A1 O’Sullivan, Brendan J.
A1 Powell, Joseph E.
A1 Calamita, Emily
A1 Ghai, Poonam
A1 Walker, Simone A.
A1 McErlean, Peter
A1 Saunders, Peter
A1 Kingston, Shaun
A1 Molyneaux, Philip L.
A1 Halket, John M.
A1 Gray, Robert
A1 Chambers, Daniel C.
A1 Maher, Toby M.
A1 Lloyd, Clare M.
A1 Byrne, Adam J.
YR 2020
UL http://immunology.sciencemag.org/content/5/52/eabc1884.abstract
AB Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease associated with accumulation of extracellular matrix in the lung. Here, Ogger et al. define a role for itaconate in regulating fibrosis. Itaconate synthesis by macrophages is catalyzed by cis-aconitate decarboxylase, which is encoded by aconitate decarboxylase 1 (ACOD1). Itaconate levels are lower in bronchoalveolar lavage, and ACOD1 expression is decreased in alveolar macrophages (AMs) of patients with IPF compared with controls. Acod1−/− mice develop severe pulmonary fibrosis relative to wild-type (WT) littermates, and adoptive transfer of WT, but not Acod1−/−, Mo-AMs into Acod1−/− mice rescued the fibrotic phenotype. Treatment of Acod1−/− mice with inhaled itaconate also had an antifibrotic effect. These findings highlight a role for itaconate in controlling lung fibrosis, revealing a pathway for potential therapeutics.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.