RTN3 regulates collagen biosynthesis and profibrotic macrophage differentiation to promote pulmonary fibrosis via interacting with CRTH2.

Abstract

Background: As an endoplasmic reticulum (ER) protein, Reticulum 3 (RTN3) has been reported to play a crucial role in neurodegenerative diseases, lipid metabolism, and chronic kidney disease. The involvement of RTN3 in idiopathic pulmonary fibrosis (IPF), a progressive and fatal interstitial lung disease, remains unexplored.

Methods: In this study, we explored the role of RTN3 in pulmonary fibrosis using public datasets, IPF patient samples, and animal models. We investigated its pathogenic mechanisms in lung fibroblasts and alveolar macrophages.

Results: We found decreased levels of RTN3 in IPF patients, bleomycin-induced mice, and TGFβ-treated cell lines. RTN3-null mice exhibited more severe pulmonary fibrosis phenotypes in old age or after bleomycin treatment. Collagen synthesis was significantly increased in RTN3-null mice lung tissues and lung fibroblasts. Mechanistic studies revealed that RTN3 deficiency reduced the ER-anchored CRTH2 in lung fibroblasts, which serves as an antifibrotic molecule via antagonizing collagen biosynthesis. Simultaneously, RTN3 deficiency reduced the autophagy degradation of CRTH2 which acts as an activator of profibrotic macrophage differentiation. Both effects of RTN3 and CRTH2 in lung fibroblasts and alveolar macrophages aggravated age-or bleomycin-induced pulmonary fibrosis. Additionally, we also identified a mutation of RTN3 in patients with ILD.

Conclusions: Our research demonstrated that RTN3 plays a significant role in the lung, and reduction of RTN3 levels may be a risk factor for IPF and related diseases.