Abstract
Idiopathic pulmonary fibrosis (IPF), a chronic disease of unknown cause, is characterized by abnormal accumulation of extracellular matrix (ECM) in fibrotic foci in the lung. Previous studies have shown that the transforming growth factor β1 (TGFβ1) and signal transducers and activators of transcription (STAT) pathways play roles in IPF pathogenesis. Glutamyl-prolyl-tRNA-synthetase (EPRS) has been identified as a target for anti-fibrosis therapy, but the link between EPRS and TGFβ1-mediated IPF pathogenesis remains unknown. Here, we studied the role of EPRS in the development of fibrotic phenotypes in A549 alveolar epithelial cells and bleomycin-treated animal models. We found that EPRS knockdown inhibited the TGFβ1-mediated upregulation of fibronectin and collagen I and the mesenchymal proteins α-smooth muscle actin (α-SMA) and snail 1. TGFβ1-mediated transcription of collagen I-α1 and laminin γ2 in A549 cells was also down-regulated by EPRS suppression, indicating that EPRS is required for ECM protein transcriptions. Activation of STAT signaling in TGFβ1-induced ECM expression was dependent on EPRS. TGFβ1 treatment resulted in EPRS-dependent in vitro formation of a multi-protein complex consisting of the TGFβ1 receptor, EPRS, Janus tyrosine kinases (JAKs), and STATs. In vivo lung tissue from bleomycin-treated mice showed EPRS-dependent STAT6 phosphorylation and ECM production. Our results suggest that epithelial EPRS regulates the expression of mesenchymal markers and ECM proteins via the TGFβ1/STAT signaling pathway. Therefore, epithelial EPRS can be used as a potential target to develop anti-IPF treatments.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fatal, fibrotic interstitial lung disease of unknown cause (Zhou et al, 2017; Bai et al, 2018; Lederer and Martinez, 2018; Milara et al, 2018)
Since EPRS protein consists of two glutamyltRNA-synthetase (ERS) and prolyl-transfer RNA (tRNA)-synthetase (PRS), it would be reasonable to see whether Prolyl-tRNA synthetase (PRS) alone could achieve these effects
Our results suggest that EPRS positively regulated transforming growth factor β1 (TGFβ1)-induced expression of extracellular matrix (ECM) proteins
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fatal, fibrotic interstitial lung disease of unknown cause (Zhou et al, 2017; Bai et al, 2018; Lederer and Martinez, 2018; Milara et al, 2018). Idiopathic pulmonary fibrosis (IPF) is characterized by the excessive accumulation of extracellular matrix (ECM) components, which correlates with the proliferation and activation of fibroblasts, myofibroblasts, and abnormal lung epithelial cells (Wolters et al, 2014). Current pharmacologic treatments for IPF include two U.S Food & Drug Administration-approved drugs (nintedanib and pirfenidone) that improve symptoms but do not cure the disease (Lederer and Martinez, 2018). Given the limited treatment options, it is urgent to investigate the mechanisms of IPF pathogenesis (Milara et al, 2018)
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