The NADPH oxidase DUOX1 contributes to profibrotic macrophage activation and pulmonary fibrosis

Fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by various forms of environmental injury and involve reciprocal interactions between activated (myo)fibroblasts and recruited monocyte-derived macrophages (MoMacs), collectively leading to progressive tissue remodeling. Extending previous findings implicating redox-based mechanisms in IPF pathogenesis, we here highlight the involvement of the NADPH oxidase (NOX) homolog DUOX1 in pulmonary fibrosis, based on observed increases in DUOX1 expression within fibrotic regions of IPF lung tissues or lung tissues from mice with experimentally induced pulmonary fibrosis, localized primarily to (myo)fibroblasts and recruited MoMacs. Building on a previous report implicating DUOX1 in myofibroblast activation, conditional DUOX1 ablation from myeloid cells (including macrophages) using LysM-Cre was found to dramatically attenuate fibrosis, highlighted by impaired MoMac recruitment, reduced collagen production, and improved oxygen saturation. A macrophage-intrinsic role of DUOX1 was further supported by its observed contribution to in vitro migration of bone marrow-derived macrophages (BMDM) and to profibrotic BMDM activation, the latter including production of several epidermal growth factor receptor ligands involved in macrophage-fibroblast cross-talk. Finally, these DUOX1-mediated actions were associated with oxidative activation of Src kinase via cysteine oxidation, and were inhibitable by saracatinib, a clinically used Src inhibitor. Collectively, our findings highlight the involvement of DUOX1 in macrophage-(myo)fibroblast cross-talk in the pathogenesis and/or progression of pulmonary fibrosis, implicating it as a putatively novel therapeutically targetable feature of this devastating disease.