Inhibition of sphingosine‐1‐phosphate receptor‐2 attenuates chronic gastritis via blocking nuclear translocation of S1P 2 receptors in epithelial cells

Abstract Background and Purpose Although there is a decline in the overall incidence of chronic gastritis through antibiotic treatment, the public health burden remains significant because of low eradication rates. Herein, we explore the role of sphingosine‐1‐phosphate receptor‐2 (S1P 2 receptor) in mediating the development of chronic gastritis, as well as the effect of S1P 2 receptor antagonists in attenuating its development. Experimental Approach Chronic gastritis model was established through long‐term exposure to lipopolysaccharide (LPS) in mice. S1P 2 receptor antagonists were administrated via gavage. Western blotting and immunohistochemistry assays analysed S1P 2 receptor and paralemmin‐3 (PALM3). Co‐immunoprecipitation and immunofluorescence staining assays identified the binding of S1P 2 receptor with NF‐kappa‐B‐activating protein (NKAP) or PALM3 in the nuclei. Haematoxylin–eosin staining assessed gastric tissues. 16S ribosomal RNA gene amplicon sequencing analysed gastric microbiota compositions. Key Results Long‐term exposure to LPS developed chronic gastritis by activating S1P 2 receptors in gastric epithelial cells. Mechanistically, LPS stimulated PALM3‐mediated nuclear translocation of S1P 2 receptors, which then bound to NKAP; leading to the upregulation of NF‐ κ B/IL‐6 pathway. Inhibition of S1P 2 receptors blocked LPS‐induced nuclear translocation, resulting in downregulation of NF‐ κ B/IL‐6 pathway. Administration of S1P 2 receptor antagonists attenuated the LPS‐induced chronic gastritis. Additionally, abundance of pathogenic Gram‐negative gastric bacteria (e.g., Enterobacter ) was significantly reduced following treatment with S1P 2 receptor antagonists. Conclusions and Implications Long‐term exposure to LPS developed chronic gastritis by stimulating S1P 2 receptors. S1P 2 receptors thus represent a potential target for treatment of chronic gastritis. S1P 2 receptor antagonist blocks the LPS‐induced nuclear translocation of S1P 2 receptors, thus attenuating chronic gastritis.