British journal of pharmacology · 2025
Inhibition of sphingosine-1-phosphate receptor-2 attenuates chronic gastritis via blocking nuclear translocation of S1P2 receptors in epithelial cells.
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Li Ke-Qin, Sun Zhi-Meng, Shao Han-Bing, Tan Ming-Yong, Yang Ming, He Cheng-Wei, Cheng Yu-Yao, Zhang Xi-Nan, Jiang Lei-Lei, Wan Sheng-Biao, Cui Shu-Xiang, Qu Xian-Jun
Аннотация
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.
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.