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.

The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities

“…Itaconate was also found to alleviate idiopathic pulmonary fibrosis (IPF) through changing macrophage phenotype and function (Wynn and Vannella, 2016 ; Allden et al, 2019 ). A recent study found that the expression of ACOD1/itaconate was obviously reduced in patients with IPF, this reduction was proved to exacerbate more disease severity of pulmonary fibrosis in mice (Ogger et al, 2020 ). Administration or inhalation of exogenous itaconate reversed the formulation of pulmonary fibrosis through changing the fibroblast metabolic phenotype, decreased proliferative capacity, and limited wound healing of human lung fibroblasts.…”

IRF5 regulates airway macrophage metabolic responses

“…In influenza models in mice, infiltrating monocyte‐derived AMs (Mo‐AMs) have been shown to be more glycolytic, in comparison to tissue‐resident AMs (TR‐AMs) [21]. Indeed, our recent work has shown that TR‐AMs more readily engage OxPhos, in comparison to recruited Mo‐AMs, in the context of lung fibrosis [23].…”

Regulatory Immune Cells in Idiopathic Pulmonary Fibrosis: Friends or Foes?

“…Acod1 deficient mice developed more severe BPF, while adoptive transfer of lung-derived monocytic macrophages from healthy donor mice alleviated the developed persistent fibrosis (157). Furthermore, itaconate was shown to decrease fibroblast proliferation and wound healing capacity of cultured fibroblasts (157).…”

“…On the other hand, itaconate has recently been described to mediate anti-fibrotic effects of macrophages in the lungs (157). Decreased levels of pulmonary itaconate as well as reduced itaconate-synthesizing cis-aconitate decarboxylase (ACOD1) expression (which mediates itaconate production) in lung macrophages were observed in IPF patients (157).…”

“…On the other hand, itaconate has recently been described to mediate anti-fibrotic effects of macrophages in the lungs (157). Decreased levels of pulmonary itaconate as well as reduced itaconate-synthesizing cis-aconitate decarboxylase (ACOD1) expression (which mediates itaconate production) in lung macrophages were observed in IPF patients (157). Acod1 deficient mice developed more severe BPF, while adoptive transfer of lung-derived monocytic macrophages from healthy donor mice alleviated the developed persistent fibrosis (157).…”