Inhibition of sphingosine-1-phosphate receptor-2 attenuates chronic gastritis via blocking nuclear translocation of S1P2 receptors in epithelial cells

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 (S1P₂ receptor) in mediating the development of chronic gastritis, as well as the effect of S1P₂ receptor antagonists in attenuating its development.

Experimental approach: Chronic gastritis model was established through long-term exposure to lipopolysaccharide (LPS) in mice. S1P₂ receptor antagonists were administrated via gavage. Western blotting and immunohistochemistry assays analysed S1P₂ receptor and paralemmin-3 (PALM3). Co-immunoprecipitation and immunofluorescence staining assays identified the binding of S1P₂ 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 S1P₂ receptors in gastric epithelial cells. Mechanistically, LPS stimulated PALM3-mediated nuclear translocation of S1P₂ receptors, which then bound to NKAP; leading to the upregulation of NF-κB/IL-6 pathway. Inhibition of S1P₂ receptors blocked LPS-induced nuclear translocation, resulting in downregulation of NF-κB/IL-6 pathway. Administration of S1P₂ 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 S1P₂ receptor antagonists.

Conclusions and implications: Long-term exposure to LPS developed chronic gastritis by stimulating S1P₂ receptors. S1P₂ receptors thus represent a potential target for treatment of chronic gastritis. S1P₂ receptor antagonist blocks the LPS-induced nuclear translocation of S1P₂ receptors, thus attenuating chronic gastritis.

NKAP; PALM3; S1P2 receptor; S1P2 receptor antagonist; chronic gastritis; gram‐negative gastric microbiota; lipopolysaccharides (LPS).