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. 2025 Apr 13.
doi: 10.1111/bph.70043. Online ahead of print.

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

Si-Yuan Mu  1 , Rui Xu  1 , Xin-Feng Wu  1 , Yu-Yao Cheng  2 , Zhi-Meng Sun  1 , Han-Tao Liu  1 , Han-Bing Shao  2 , Xiao-Nan Zhang  3 , Xi-Nan Zhang  2 , Ming Yang  1 , Ming-Yong Tan  2 , Wei-Shi Liang  4 , Sheng-Biao Wan  5 , Shu-Xiang Cui  2 , Xian-Jun Qu  1
Affiliations

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

Si-Yuan Mu et al. Br J Pharmacol. .

Abstract

Background and purpose: Activation of the sphingosine-1-phosphate receptor-2 (S1P2 receptor) promotes idiopathic pulmonary fibrosis (IPF). However, the mechanisms associated with IPF development via S1P2 receptor signalling are poorly understood and no S1P2 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 S1P2 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 S1P2 receptors promoted IPF through the binding of S1P2 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 S1P2 receptor to Dpr1 also led to S1P2 receptor translocation to the nucleus, where it promoted EMT by activating CREB1. BLM-induced IPF in mice was characterised by activated-S1P2 receptor signalling. Inhibition of S1P2 receptor prevented the binding of S1P2 receptor to Dpr1, resulting in decreased β-catenin accumulation and blocking nuclear translocation of S1P2 receptor. The S1P2 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 S1P2 receptors promotes IPF through the binding of S1P2 receptor to Dpr1 and the nuclear translocation of S1P2 receptor to activate CREB1. Thus, the S1P2 receptor antagonist S118 has potential clinical application in attenuating IPF.

Keywords: Dapper1 (Dpr1); S1P2 receptor antagonist; Sphingosine‐1‐phosphate receptor‐2 (S1P2 receptor); Wnt/β‐catenin pathway; epithelial–mesenchymal transition (EMT); idiopathic pulmonary fibrosis (IPF).

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