FOXL1 Regulates Lung Fibroblast Function Via Multiple Mechanisms

Abstract

Fibroblasts provide a structural framework for multiple organs and are essential for wound repair and fibrotic processes. Here, we demonstrate functional roles of FOXL1 (forkhead box L1), a transcription factor that characterizes the pulmonary origin of lung fibroblasts. We detected high <i>FOXL1</i> transcripts associated with DNA hypomethylation and super-enhancer formation in lung fibroblasts, which is in contrast with fibroblasts derived from other organs. RNA <i>in situ</i> hybridization and immunohistochemistry in normal lung tissue indicated that FOXL1 mRNA and protein are expressed in submucosal interstitial cells together with airway epithelial cells. Transcriptome analysis revealed that FOXL1 could control a broad array of genes that potentiate fibroblast function, including TAZ (transcriptional coactivator with PDZ-binding motif)/YAP (Yes-associated protein) signature genes and PDGFRα (platelet-derived growth factor receptor-α). <i>FOXL1</i> silencing in lung fibroblasts attenuated cell growth and collagen gel contraction capacity, underscoring the functional importance of FOXL1 in fibroproliferative reactions. Of clinical importance, increased <i>FOXL1</i> mRNA expression was found in fibroblasts of idiopathic pulmonary fibrosis lung tissue. Our observations suggest that FOXL1 regulates multiple functional aspects of lung fibroblasts as a key transcription factor and is involved in idiopathic pulmonary fibrosis pathogenesis.