Inflammation-associated senescence promotes Helicobacter pylori-induced atrophic gastritis.

Abstract Background & Aims The association between cellular senescence and Helicobacter pylori (H. pylori)-induced atrophic gastritis is not clear. Here, we explore the role of cellular senescence in H. pylori-induced atrophic gastritis and the underlying mechanism. Methods C57BL/6J mice were infected with H. pylori for biological and mechanistic studies in vivo. Gastric precancerous lesions from patients and mouse models were collected and analyzed using SA-β-gal, Sudan Black B, and immunohistochemical staining to analyze senescent cells, signaling pathways, and H. pylori infection. Chromatin immunoprecipitation, luciferase reporter assays and other techniques were used to explore the underlying mechanism in vitro. Results Gastric mucosa atrophy was highly associated with cellular senescence. H. pylori promoted gastric epithelial cell senescence in vitro and in vivo in a manner that depended on C-X-C motif chemokine receptor 2 (CXCR2) signaling. Interestingly, H. pylori infection not only upregulated the expression of CXCR2 ligands, C-X-C motif chemokine ligand 1 (CXCL1) and 8 (CXCL8), but also transcriptionally upregulated the expression of CXCR2 via nuclear factor-kappa B subunit 1 (NFKB1) directly. In addition, CXCR2 formed a positive feedback loop with p53 to continually enhance senescence. Pharmaceutical inhibition of CXCR2 in an H. pylori-infected mouse model attenuated mucosal senescence and atrophy and delayed further precancerous lesion progression. Conclusions Our study demonstrated a new mechanism of H. pylori-induced atrophic gastritis through CXCR2-mediated cellular senescence. Inhibition of CXCR2 signaling is suggested as a potential preventive therapy for targeting H. pylori-induced atrophic gastritis.