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

<bold>Background:</bold> As an endoplasmic reticulum (ER) protein, Reticulum 3 (RTN3) was reported can play a crucial role in neurodegenerative diseases, lipid metabolism, and chronic kidney disease. However, the role of RTN3 in idiopathic pulmonary fibrosis (IPF), a progressive, lethal, interstitial lung disease, has not been explored. <bold>Methods:</bold> We employed public datasets, patient data, and animal models to explore the role of RTN3 in IPF. The underlying mechanisms were studied in primary lung fibroblasts and alveolar macrophages. <bold>Result:</bold> We found decreased levels of RTN3 in IPF patients, bleomycin-induced mice, and TGFβ treated cell lines. RTN3-null mice presented more severe pulmonary fibrosis phenotypes in old age or after bleomycin treatment. Collagen synthesis was significantly increased in the lung tissues of RTN3-null mice. Mechanistic study revealed that RTN3 deficiency reduced the ER-anchored CRTH2 in lung fibroblasts which served as an antifibrotic molecule via antagonizing collagen biosynthesis. Additionally, RTN3 deficiency reduced the selective autophagy of CRTH2 in alveolar macrophages which acted as an activator for profibrotic macrophage differentiation. Both effects of RTN3 and CRTH2 in lung fibroblasts and alveolar macrophages aggravated age or bleomycin-induced pulmonary fibrosis. <bold>Conclusions:</bold> Our study indicated that RTN3 was important in the lung and that a decrease in RTN3 in the lung might be a risk factor for IPF. Figure:RTN3-null mice presented more severe pulmonary fibrosis phenotypes at old age or after bleomycin treatment.