Inhibition of sphingosine‐1‐phosphate receptor‐2 attenuates idiopathic pulmonary fibrosis by preventing its binding to dapper1 in bronchial epithelial cells

Abstract Background and Purpose Activation of the sphingosine‐1‐phosphate receptor‐2 (S1P 2 receptor) promotes idiopathic pulmonary fibrosis (IPF). However, the mechanisms associated with IPF development via S1P 2 receptor signalling are poorly understood and no S1P 2 receptor antagonists have been approved for clinical use. Experimental Approach Western blotting and immunohistochemical assays analysed inflammatory factors and epithelial–mesenchymal transition (EMT) markers. Co‐immunoprecipitation and immunofluorescence analysed the binding of S1P 2 receptor to dapper1 (Dpr1) and cyclic AMP response‐binding protein 1 (CREB1). X‐ray‐based computed tomography diagnosed IPF in bleomycin (BLM)‐treated mice. Barometric whole‐body plethysmography tested pulmonary function of mice. Masson's trichrome and Sirius red staining analysed extracellular matrix deposition. Enzyme‐linked immunosorbent assays analysed inflammatory factors and hydroxyproline. Key Results Activation of S1P 2 receptors promoted IPF through the binding of S1P 2 receptor to Dpr1, decreasing dishevelled (Dvl) degradation to accumulate β‐catenin. The β‐catenin accumulated in the nucleus, upregulating its target genes by binding to T‐cell factor/lymphoid enhancer factor. The binding of S1 P2 receptor to Dpr1 also led to S1P 2 receptor translocation to the nucleus, where it promoted EMT by activating CREB1. BLM‐induced IPF in mice was characterised by activated‐S1P 2 receptor signalling. Inhibition of S1P 2 receptor prevented the binding of S1P2 receptor to Dpr1, resulting in decreased β‐catenin accumulation and blocking nuclear translocation of S1P 2 receptor. The S1P 2 receptor antagonist S118 was more effective than pirfenidone in attenuating IPF through anti‐inflammatory, anti‐fibrosis, and anti‐EMT effects. Conclusions and Implications Activation of S1P 2 receptors promotes IPF through the binding of S1P 2 receptor to Dpr1 and the nuclear translocation of S1P 2 receptor to activate CREB1. Thus, the S1P 2 receptor antagonist S118 has potential clinical application in attenuating IPF.